📚 Article Archive

HDL flux is higher in patients with nonalcoholic fatty liver disease.

Arthur McCullough, Stephen F Previs, Jaividhya Dasarathy +8 more · 2019 · American journal of physiology. Endocrinology and metabolism · added 2026-04-24

Arthur McCullough, Stephen F Previs, Jaividhya Dasarathy, Kwangwon Lee, Abdullah Osme, Chunki Kim, Serguei Ilchenko, Shuhui W Lorkowski, Jonathan D Smith, Srinivasan Dasarathy, Takhar Kasumov Show less

Altered lipid metabolism and inflammation are involved in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL) Show more

Altered lipid metabolism and inflammation are involved in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL protein dynamics in SS ( Show less

no PDF DOI: 10.1152/ajpendo.00193.2019

CETP

CETP, LIPC, and SCARB1 variants in individuals with extremely high high-density lipoprotein-cholesterol levels.

Chan Joo Lee, Mun Su Park, Miso Kim +7 more · 2019 · Scientific reports · Nature · added 2026-04-24

Chan Joo Lee, Mun Su Park, Miso Kim, Soo-Jin Ann, Jaeho Lee, Sungha Park, Seok-Min Kang, Yangsoo Jang, Ji Hyun Lee, Sang-Hak Lee Show less

The concentration of high-density lipoprotein-cholesterol (HDL-C) in humans is partially determined by genetic factors; however, the role of these factors is incompletely understood. The aim of this s Show more

The concentration of high-density lipoprotein-cholesterol (HDL-C) in humans is partially determined by genetic factors; however, the role of these factors is incompletely understood. The aim of this study was to examine the prevalence and characteristics of CETP, LIPC, and SCARB1 variants in Korean individuals with extremely high HDL-C levels. We also analysed associations between these variants and cholesterol efflux capacity (CEC), reactive oxygen species (ROS) generation, and vascular cell adhesion molecule-1 (VCAM-1) expression. Of 13,545 participants in the cardiovascular genome cohort, 42 subjects with HDL-C levels >100 mg/dL were analysed. The three target genes were sequenced by targeted next-generation sequencing, the functional effects of detected variants were predicted, and CEC was assessed using a radioisotope and apolipoprotein B-depleted sera. We observed two rare variants of CETP in 13 individuals (rare variant c.A1196G [p.D399G] of CETP was discovered in 12 subjects) and one rare variant of SCARB1 in one individual. Furthermore, all subjects had at least one of four common variants (one CETP and three LIPC variants). Two additional novel CETP variants of unknown frequency were found in two subjects. However, the identified variants did not show significant associations with CEC, ROS generation, or VCAM-1 expression. Our study provides additional insights into the role of genetics in individuals with extremely high HDL-C. Show less

📄 PDF DOI: 10.1038/s41598-019-47456-2

CETP

Antihyperlipidemic and Antioxidative Potentials of Onion (

Woong-Suk Yang, Jin-Chul Kim, Jae Yong Lee +2 more · 2019 · Evidence-based complementary and alternative medicine : eCAM · added 2026-04-24

Woong-Suk Yang, Jin-Chul Kim, Jae Yong Lee, Cheorl-Ho Kim, Cher-Won Hwang Show less

The purpose of this study was to investigate antihyperlipidemic and antioxidative potentials of onion (

📄 PDF DOI: 10.1155/2019/3269047

CETP

Capsular Polysaccharide Is a Receptor of a

Eunsu Ha, Jihwan Chun, Minsik Kim +1 more · 2019 · Viruses · MDPI · added 2026-04-24

Eunsu Ha, Jihwan Chun, Minsik Kim, Sangryeol Ryu Show less

📄 PDF DOI: 10.3390/v11111002

CPS1

Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population.

Tae-Joon Park, Heun-Sik Lee, Young Jin Kim +1 more · 2019 · Bioscience reports · added 2026-04-24

Tae-Joon Park, Heun-Sik Lee, Young Jin Kim, Bong-Jo Kim Show less

Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants a Show more

Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10-7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation. Show less

📄 PDF DOI: 10.1042/BSR20190078

CPS1

Author Correction: CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells.

Jiyeon Kim, Zeping Hu, Ling Cai +23 more · 2019 · Nature · Nature · added 2026-04-24

Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method Show more

Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method revealed that the level of carbamoyl phosphate in these NSCLC extracts is below the detection threshold of approximately 10 nanomoles. These findings do not alter the overall conclusions of the Letter; see associated Amendment for full details. The Letter has not been corrected online. Show less

no PDF DOI: 10.1038/s41586-019-1133-3

CPS1

Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury.

Min-jung Park, Louis G D'Alecy, Michelle A Anderson +10 more · 2019 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24

Min-jung Park, Louis G D'Alecy, Michelle A Anderson, Venkatesha Basrur, Yongjia Feng, Graham F Brady, Dong-il Kim, Jun Wu, Alexey I Nesvizhskii, Joerg Lahann, Nicholas W Lukacs, Robert J Fontana, M Bishr Omary Show less

Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life Show more

Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life. The function of CPS1 in blood and the reason for its short half-life in serum are unknown. We show that CPS1 is released normally into mouse and human bile, and pathologically into blood during acute liver injury. Other cytoplasmic and mitochondrial urea cycle enzymes are also found in normal mouse bile. Serum, bile, and purified CPS1 manifest sedimentation properties that overlap with extracellular vesicles, due to the propensity of CPS1 to aggregate despite being released primarily as a soluble protein. During liver injury, CPS1 in blood is rapidly sequestered by monocytes, leading to monocyte M2-polarization and homing to the liver independent of its enzyme activity. Recombinant CPS1 (rCPS1), but not control r-transferrin, increases hepatic macrophage numbers and phagocytic activity. Notably, rCPS1 does not activate hepatic macrophages directly; rather, it activates bone marrow and circulating monocytes that then home to the liver. rCPS1 administration prevents mouse liver damage induced by Fas ligand or acetaminophen, but this protection is absent in macrophage-deficient mice. Moreover, rCPS1 protects from acetaminophen-induced liver injury even when given therapeutically after injury induction. In summary, CPS1 is normally found in bile but is released by hepatocytes into blood upon liver damage. We demonstrate a nonenzymatic function of CPS1 as an antiinflammatory protective cytokine during acute liver injury. Show less

no PDF DOI: 10.1073/pnas.1822173116

CPS1

Human Epididymis Secretory Protein 4 (HE4) Compromises Cytotoxic Mononuclear Cells via Inducing Dual Specificity Phosphatase 6.

Nicole E James, Matthew T Oliver, Jennifer R Ribeiro +9 more · 2019 · Frontiers in pharmacology · Frontiers · added 2026-04-24

Nicole E James, Matthew T Oliver, Jennifer R Ribeiro, Evelyn Cantillo, Rachael B Rowswell-Turner, Kyu-Kwang Kim, Clinton O Chichester, Paul A DiSilvestro, Richard G Moore, Rakesh K Singh, Naohiro Yano, Ting C Zhao Show less

While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of t Show more

While selective overexpression of serum clinical biomarker Human epididymis secretory protein 4 (HE4) is indicative of ovarian cancer tumorigenesis, much is still known about the mechanistic role of the HE4 gene or gene product. Here, we examine the role of the secretory glycoprotein HE4 in ovarian cancer immune evasion. Through modified subtractive hybridization analyses of human peripheral blood mononuclear cells (PBMCs), we have characterized gene targets of HE4 and established a preliminary mechanism of HE4-mediated immune failure in ovarian tumors. Dual specificity phosphatase 6 (DUSP6) emerged as the most upregulated gene in PBMCs upon Show less

📄 PDF DOI: 10.3389/fphar.2019.00216

DUSP6

Identification of a novel mutation in EXT2 in a fourth-generation Korean family with multiple osteochondromas and overview of mutation spectrum.

Aram Yang, Jinsup Kim, Ja-Hyun Jang +4 more · 2019 · Annals of human genetics · Blackwell Publishing · added 2026-04-24

Aram Yang, Jinsup Kim, Ja-Hyun Jang, Chung Lee, Ji-Eun Lee, Sung Yoon Cho, Dong-Kyu Jin Show less

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from Show more

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype-phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four-generation Korean family with 11 MO-affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate-to-severe phenotypes (clinical classes II-III), including bony deformities and limb misalignment with pain requiring surgical correction. The x-rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic-genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient. Show less

no PDF DOI: 10.1111/ahg.12298

EXT1

Study on the fatty acid profile of phospholipid and neutral lipid in Hanwoo beef and their relationship to genetic variation.

Seok-Hyeon Beak, Yoonseok Lee, Eun Bi Lee +4 more · 2019 · Journal of animal science and technology · added 2026-04-24

Seok-Hyeon Beak, Yoonseok Lee, Eun Bi Lee, Kyoung Hoon Kim, Jong Geun Kim, Jin Duck Bok, Sang-Kee Kang Show less

Maize which has very high omega-6 fatty acid content has been used as a main feed grain for Hanwoo beef production to increase marbling, and thus omega-6 to omega-3 fatty acids ratio in Hanwoo beef is Show more

Maize which has very high omega-6 fatty acid content has been used as a main feed grain for Hanwoo beef production to increase marbling, and thus omega-6 to omega-3 fatty acids ratio in Hanwoo beef is expected to be biased. To elucidate the current status of omega fatty acids ratio in Hanwoo beef, fatty acid profiles of neutral lipid and phospholipid fraction were analyzed separately using 55 Hanwoo steers' Show less

📄 PDF DOI: 10.5187/jast.2019.61.2.69

FADS1

Spheroid-Induced Epithelial-Mesenchymal Transition Provokes Global Alterations of Breast Cancer Lipidome: A Multi-Layered Omics Analysis.

Yun Pyo Kang, Jung-Ho Yoon, Nguyen Phuoc Long +11 more · 2019 · Frontiers in oncology · Frontiers · added 2026-04-24

Yun Pyo Kang, Jung-Ho Yoon, Nguyen Phuoc Long, Gi-Bang Koo, Hyun-Jin Noh, Seung-Jae Oh, Sae Bom Lee, Hyung Min Kim, Ji Yeon Hong, Won Jun Lee, Seul Ji Lee, Soon-Sun Hong, Sung Won Kwon, You-Sun Kim Show less

Metabolic rewiring has been recognized as an important feature to the progression of cancer. However, the essential components and functions of lipid metabolic networks in breast cancer progression ar Show more

Metabolic rewiring has been recognized as an important feature to the progression of cancer. However, the essential components and functions of lipid metabolic networks in breast cancer progression are not fully understood. In this study, we investigated the roles of altered lipid metabolism in the malignant phenotype of breast cancer. Using a spheroid-induced epithelial-mesenchymal transition (EMT) model, we conducted multi-layered lipidomic and transcriptomic analysis to comprehensively describe the rewiring of the breast cancer lipidome during the malignant transformation. A tremendous homeostatic disturbance of various complex lipid species including ceramide, sphingomyelin, ether-linked phosphatidylcholines, and ether-linked phosphatidylethanolamine was found in the mesenchymal state of cancer cells. Noticeably, polyunsaturated fatty acids composition in spheroid cells was significantly decreased, accordingly with the gene expression patterns observed in the transcriptomic analysis of associated regulators. For instance, the up-regulation of Show less

📄 PDF DOI: 10.3389/fonc.2019.00145

FADS1

Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD

Wondong Kim, Amy Deik, Clicerio Gonzalez +8 more · 2019 · Cell metabolism · Elsevier · added 2026-04-24

Wondong Kim, Amy Deik, Clicerio Gonzalez, Maria Elena Gonzalez, Feifei Fu, Michele Ferrari, Claire L Churchhouse, Jose C Florez, Suzanne B R Jacobs, Clary B Clish, Eugene P Rhee Show less

The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD

📄 PDF DOI: 10.1016/j.cmet.2018.12.023

FADS1

Low-linoleic acid diet and oestrogen enhance the conversion of α-linolenic acid into DHA through modification of conversion enzymes and transcription factors.

Donghee Kim, Jeong-Eun Choi, Yongsoon Park · 2019 · The British journal of nutrition · added 2026-04-24

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the p Show more

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the purpose of this study was to evaluate the effect of a low-LA diet with and without oestrogen on the fatty acid conversion enzymes and transcription factors. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFA or ALA, containing low or high amounts of LA for 12 weeks. At 8 weeks, the rats were injected with maize oil with or without 17β-oestradiol-3-benzoate (E) at constant intervals for the remaining 3 weeks. Both the low-LA diet and E significantly increased the hepatic expressions of PPAR-α, fatty acid desaturase (FADS) 2, elongase of very long chain fatty acids 2 (ELOVL2) and ELOVL5 but decreased sterol regulatory element binding protein 1. The low-LA diet, but not E, increased the hepatic expression of FADS1, and E increased the hepatic expression of oestrogen receptor-α and β. The low-LA diet and E had synergic effects on serum and liver levels of DHA and on the hepatic expression of PPAR-α. In conclusion, the low-LA diet and oestrogen increased the conversion of ALA into DHA by upregulating the elongases and desaturases of fatty acids through regulating the expression of transcription factors. The low-LA diet and E had a synergic effect on serum and liver levels of DHA through increasing the expression of PPAR-α. Show less

no PDF DOI: 10.1017/S0007114518003252

FADS1

Carrying minor allele of FADS1 and haplotype of FADS1 and FADS2 increased the risk of metabolic syndrome and moderate but not low fat diets lowered the risk in two Korean cohorts.

Sunmin Park, Da Sol Kim, Suna Kang · 2019 · European journal of nutrition · Springer · added 2026-04-24

Delta-5-desaturase (fatty acid desaturase-1, FADS1) and delta-6 desaturase (fatty acid desaturase-2, FADS2), rate-limiting enzymes in the biosynthesis of long-chain polyunsaturated fatty acids, may be Show more

Delta-5-desaturase (fatty acid desaturase-1, FADS1) and delta-6 desaturase (fatty acid desaturase-2, FADS2), rate-limiting enzymes in the biosynthesis of long-chain polyunsaturated fatty acids, may be associated with the risk of metabolic syndrome (MetS). We investigated how FADS1 rs174547 and FADS2 rs2845573 variants modify the prevalence of MetS and whether the risk is modulated by interactions with dietary fat. Genetic, anthropometric, biochemical, and dietary data were collected from the Ansan/Ansung (8842 adults) and City-Rural (5512 adults) cohorts in Korea. The association between FADS1 rs174547(C/T) and FADS2 rs2845573(C/T) variants and MetS was analyzed, as was the interaction of genotypes and fatty acid intake and the risk of MetS after adjusting for MetS-related confounders. Carriers of FADS1 rs174547 and FADS2 rs2845573 minor alleles had lower serum HDL-cholesterol and glucose levels and higher triglyceride levels than those with major alleles. Ansan/Ansung cohort individuals with FADS1 minor alleles or haplotypes of FADS1 and FADS2 minor alleles had increased risk of MetS, including lower serum HDL-cholesterol and triglyceride levels and blood pressure after adjusting for MetS-related confounders. The City-Rural cohort showed similar results. Total fat intake showed interactions with FADS1 and haplotype variants on MetS risk: MetS frequency was reduced in people consuming moderate fat diets as compared to low fat diets in FADS1 and haplotype of FADS1 and FADS2 major alleles. Korean carriers of the FADS1 rs174547 and FADS2 rs2845573 minor alleles have a greater susceptibility to MetS and moderate fat intake protected against the risk of MetS in carriers of the FADS1 major alleles. Show less

no PDF DOI: 10.1007/s00394-018-1719-9

FADS1

Expression of steroidogenic enzymes in human placenta according to the gestational age.

So-Hye Hong, Seung Chul Kim, Mee-Na Park +8 more · 2019 · Molecular medicine reports · added 2026-04-24

So-Hye Hong, Seung Chul Kim, Mee-Na Park, Jea Sic Jeong, Seung Yun Yang, Young Joo Lee, Ok-Nam Bae, Hoe-Saeng Yang, Sungbaek Seo, Kyu-Sup Lee, Beum-Soo An Show less

Female sex steroid hormones, including estradiol (E2) and progesterone (P4), serve significant physiological roles in pregnancy. In particular, E2 and P4 influence placenta formation, maintain pregnan Show more

Female sex steroid hormones, including estradiol (E2) and progesterone (P4), serve significant physiological roles in pregnancy. In particular, E2 and P4 influence placenta formation, maintain pregnancy and stimulate milk production. These hormones are produced by ovaries, adrenal glands and the placenta, of which the latter is a major endocrine organ during pregnancy. However, the mechanism of hormone production during pregnancy remains unclear. In the present study, the regulation of steroid hormones and steroidogenic enzymes was examined in human placenta according to gestational age. In human placental tissues, expression levels of steroidogenic enzymes were determined with reverse transcription‑quantitative polymerase chain reaction and western blotting. The mRNA and protein expression of CYP17A1, HSD17B3 and CYP19A1, which are associated with the synthesis of dehydroepiandrosterone (DHEA) and E2, was elevated at different gestational ages in human placenta. In addition, to evaluate the correlation between serum and placental‑produced hormones, steroid hormone levels, including pregnenolone (PG), DHEA, P4, testosterone (T) and E2, were examined in serum and placenta. Serum and placenta expression of DHEA and E2 increased with gestational age, whereas T and P4 were differently regulated in placenta and serum. To confirm the mechanism of steroidogenesis in vitro, placental BeWo cells were treated with E2 and P4, which are the most important hormones during pregnancy. The mRNA and protein expression of steroidogenic enzymes was significantly altered by E2 in vitro. These results demonstrated that concentration of steroid hormones was differently regulated by steroidogenic enzymes in the placenta depending on the type of the hormones, which may be critical to maintain pregnancy. Show less

no PDF DOI: 10.3892/mmr.2019.10048

HSD17B12

Histone Lys demethylase KDM3C demonstrates anti-inflammatory effects by suppressing NF-κB signaling and osteoclastogenesis.

Jae Young Lee, Shebli Mehrazarin, Abdullah Alshaikh +6 more · 2019 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24

Jae Young Lee, Shebli Mehrazarin, Abdullah Alshaikh, Sol Kim, Wei Chen, Renate Lux, Yousang Gwack, Reuben H Kim, Mo K Kang Show less

Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is Show more

Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is poorly understood. Here, we show a novel regulatory role of KDM3C in inflammatory responses to oral bacterial infection. KDM3C expression is transiently suppressed in human and mouse macrophages exposed to LPS from Show less

no PDF DOI: 10.1096/fj.201900154RR

JMJD1C

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight.

Sara Bandres-Ciga, Sarah Ahmed, Marya S Sabir +94 more · 2019 · Movement disorders : official journal of the Movement Disorder Society · Wiley · added 2026-04-24

Sara Bandres-Ciga, Sarah Ahmed, Marya S Sabir, Cornelis Blauwendraat, Astrid D Adarmes-Gómez, Inmaculada Bernal-Bernal, Marta Bonilla-Toribio, Dolores Buiza-Rueda, Fátima Carrillo, Mario Carrión-Claro, Pilar Gómez-Garre, Silvia Jesús, Miguel A Labrador-Espinosa, Daniel Macias, Carlota Méndez-Del-Barrio, Teresa Periñán-Tocino, Cristina Tejera-Parrado, Laura Vargas-González, Monica Diez-Fairen, Ignacio Alvarez, Juan Pablo Tartari, Mariateresa Buongiorno, Miquel Aguilar, Ana Gorostidi, Jesús Alberto Bergareche, Elisabet Mondragon, Ana Vinagre-Aragon, Ioana Croitoru, Javier Ruiz-Martínez, Oriol Dols-Icardo, Jaime Kulisevsky, Juan Marín-Lahoz, Javier Pagonabarraga, Berta Pascual-Sedano, Mario Ezquerra, Ana Cámara, Yaroslau Compta, Manel Fernández, Rubén Fernández-Santiago, Esteban Muñoz, Eduard Tolosa, Francesc Valldeoriola, Isabel Gonzalez-Aramburu, Antonio Sanchez Rodriguez, María Sierra, Manuel Menéndez-González, Marta Blazquez, Ciara Garcia, Esther Suarez-San Martin, Pedro García-Ruiz, Juan Carlos Martínez-Castrillo, Lydia Vela-Desojo, Clara Ruz, Francisco Javier Barrero, Francisco Escamilla-Sevilla, Adolfo Mínguez-Castellanos, Debora Cerdan, Cesar Tabernero, Maria Jose Gomez Heredia, Francisco Perez Errazquin, Manolo Romero-Acebal, Cici Feliz, Jose Luis Lopez-Sendon, Marina Mata, Irene Martínez Torres, Jonggeol Jeffrey Kim, Clifton L Dalgard, American Genome Center, Janet Brooks, Sara Saez-Atienzar, J Raphael Gibbs, Rafael Jorda, Juan A Botia, Luis Bonet-Ponce, Karen E Morrison, Carl Clarke, Manuela Tan, Huw Morris, Connor Edsall, Dena Hernandez, Javier Simon-Sanchez, Mike A Nalls, Sonja W Scholz, Adriano Jimenez-Escrig, Jacinto Duarte, Francisco Vives, Raquel Duran, Janet Hoenicka, Victoria Alvarez, Jon Infante, Maria José Marti, Jordi Clarimón, Adolfo López de Munain, Pau Pastor, Pablo Mir, Andrew Singleton, International Parkinson Disease Genomics Consortium Show less

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative disease Show more

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. Show less

📄 PDF DOI: 10.1002/mds.27864

KANSL1

Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders.

Mi-Ryung Han, Kyu-Man Han, Aram Kim +7 more · 2019 · Journal of affective disorders · Elsevier · added 2026-04-24

Mi-Ryung Han, Kyu-Man Han, Aram Kim, Wooyoung Kang, Youbin Kang, June Kang, Eunsoo Won, Woo-Suk Tae, Yunjung Cho, Byung-Joo Ham Show less

Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the asso Show more

Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts. Show less

no PDF DOI: 10.1016/j.jad.2019.02.028

MACF1

Inhibition of MEK5 suppresses TDP-43 toxicity via the mTOR-independent activation of the autophagy-lysosome pathway.

Myungjin Jo, Shinrye Lee, Kiyoung Kim +3 more · 2019 · Biochemical and biophysical research communications · Elsevier · added 2026-04-24

Myungjin Jo, Shinrye Lee, Kiyoung Kim, Seongsoo Lee, Sang Ryong Kim, Hyung-Jun Kim Show less

The most prominent hallmarks of many neurodegenerative diseases are the accumulation of misfolded protein aggregates and the death of certain neuronal populations. Autophagy is the major intracellular Show more

The most prominent hallmarks of many neurodegenerative diseases are the accumulation of misfolded protein aggregates and the death of certain neuronal populations. Autophagy is the major intracellular mechanism that degrades protein aggregates and damaged cellular components. Many studies have reported that the dysfunction of autophagy is associated with several neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. Here, we identified a novel mechanism of autophagy regulation. Inhibition of MEK5 reduced the level of p62 and increased the ratio of LC3-II to LC3-I, which is a marker for the activation of the autophagy-lysosome pathway (ALP). One of the most well-known regulators of the ALP is mTOR, and previous studies have reported that the major substrate of MEK5 is ERK5. However, we found that MEK5 modulates the autophagy-lysosome pathway in an mTOR- and ERK5-independent manner. Moreover, MEK5 inhibition alleviated the mislocalization of TDP-43 (an ALS-associated protein) and cell death in TDP-43-GFP-expressing neuronal cells. Taken together, these findings suggest that MEK5 is a novel autophagy modulator and that this kinase could be a therapeutic target for neurodegenerative diseases such as amyotrophic lateral sclerosis. Show less

no PDF DOI: 10.1016/j.bbrc.2019.04.088

MAP2K5

Clinical Evaluation of Massively Parallel RNA Sequencing for Detecting Recurrent Gene Fusions in Hematologic Malignancies.

Borahm Kim, Hyeonah Lee, Saeam Shin +2 more · 2019 · The Journal of molecular diagnostics : JMD · Elsevier · added 2026-04-24

Borahm Kim, Hyeonah Lee, Saeam Shin, Seung-Tae Lee, Jong Rak Choi Show less

The application of next-generation sequencing (NGS) technology in clinical diagnostics should proceed with care. We have evaluated the clinical validity of two commercially available RNA fusion panels Show more

The application of next-generation sequencing (NGS) technology in clinical diagnostics should proceed with care. We have evaluated the clinical validity of two commercially available RNA fusion panels, the TruSight RNA fusion panel (Illumina) and FusionPlex Pan-Heme Kit (ArcherDx), to detect recurrent translocations in hematologic malignancies. Twenty-four bone marrow samples taken at the initial diagnosis of patients with acute leukemia and chronic myeloid leukemia were included. To assess the limit of detection, serial dilutions of BCR-ABL1 (e1a2)-positive RNAs were prepared using a commercial reference material. Both NGS panels detected 19 cases with recurrent translocations identified with RT-PCR, as well as a case with KMT2A-AFF1 with false-negative results on RT-PCR. Two rare translocations, DDX3X-MLLT10 and NUP98-HOXC13, were additionally identified using NGS panels. The detection limit ranged from 10 Show less

no PDF DOI: 10.1016/j.jmoldx.2018.09.002

MLLT10

FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells.

Jung-Hwa Han, Suji Kim, Sujin Kim +3 more · 2019 · International journal of molecular sciences · MDPI · added 2026-04-24

Jung-Hwa Han, Suji Kim, Sujin Kim, Heejung Lee, So-Young Park, Chang-Hoon Woo Show less

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell Show more

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications. Show less

📄 PDF DOI: 10.3390/ijms20184424

MLXIPL

The Liver X Receptor Is Upregulated in Monocyte-Derived Macrophages and Modulates Inflammatory Cytokines Based on LXR

Hyoun-Ah Kim, Wook-Young Baek, Mi-Hwa Han +2 more · 2019 · Mediators of inflammation · added 2026-04-24

Hyoun-Ah Kim, Wook-Young Baek, Mi-Hwa Han, Ju-Yang Jung, Chang-Hee Suh Show less

Liver X receptors (LXRs) have emerged as important regulators of inflammatory gene expression. Previously, we had reported that an LXR

no PDF DOI: 10.1155/2019/6217548

NR1H3

USP37 is a SNAI1 deubiquitinase.

Zhenna Xiao, Liang Chang, Jongchan Kim +10 more · 2019 · American journal of cancer research · added 2026-04-24

Zhenna Xiao, Liang Chang, Jongchan Kim, Peijing Zhang, Qinglei Hang, Shannon Yap, Youming Guo, Zhicheng Zhou, Liyong Zeng, Xiaoyu Hu, Ashley Siverly, Yutong Sun, Li Ma Show less

SNAI1, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, promotes tumor metastasis and resistance to apoptosis and chemotherapy. SNAI1 protein levels are tightly regulated by p Show more

SNAI1, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, promotes tumor metastasis and resistance to apoptosis and chemotherapy. SNAI1 protein levels are tightly regulated by proteolytic ubiquitination. Here, we identified USP37 as a SNAI1 deubiquitinase that removes the polyubiquitination chain from SNAI1 and prevents its proteasomal degradation. USP37 directly binds, deubiquitinates, and stabilizes SNAI1. Overexpression of wild-type USP37, but not its catalytically inactive mutant C350S, promotes cancer cell migration. Importantly, depletion of USP37 downregulates endogenous SNAI1 protein and suppresses cell migration, which can be reversed by re-expression of SNAI1. Taken together, our findings suggest that USP37 is a SNAI1 deubiquitinase and a potential therapeutic target to inhibit tumor metastasis. Show less

no PDF

SNAI1

Bee Venom Suppresses EGF-Induced Epithelial-Mesenchymal Transition and Tumor Invasion in Lung Cancer Cells.

Yun-Jeong Jeong, Yoon-Yub Park, Kwan-Kyu Park +3 more · 2019 · The American journal of Chinese medicine · added 2026-04-24

Yun-Jeong Jeong, Yoon-Yub Park, Kwan-Kyu Park, Yung Hyun Choi, Cheorl-Ho Kim, Young-Chae Chang Show less

Bee venom of

no PDF DOI: 10.1142/S0192415X19500952

SNAI1

PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by

Hoon-In Choi, Jung Sun Park, Dong-Hyun Kim +4 more · 2019 · International journal of molecular sciences · MDPI · added 2026-04-24

Hoon-In Choi, Jung Sun Park, Dong-Hyun Kim, Chang Seong Kim, Eun Hui Bae, Seong Kwon Ma, Soo Wan Kim Show less

TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Rec Show more

TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or Show less

no PDF DOI: 10.3390/ijms20205084

SNAI1

Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction.

John R Ussher, Jonathan E Campbell, Erin E Mulvihill +13 more · 2018 · Cell metabolism · Elsevier · added 2026-04-24

John R Ussher, Jonathan E Campbell, Erin E Mulvihill, Laurie L Baggio, Holly E Bates, Brent A McLean, Keshav Gopal, Megan Capozzi, Bernardo Yusta, Xiemin Cao, Safina Ali, Minsuk Kim, M Golam Kabir, Yutaka Seino, Jinya Suzuki, Daniel J Drucker Show less

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely Show more

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr Show less

no PDF DOI: 10.1016/j.cmet.2017.11.003

GIPR

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Valérie Turcot, Yingchang Lu, Heather M Highland +408 more · 2018 · Nature genetics · Nature · added 2026-04-24

Valérie Turcot, Yingchang Lu, Heather M Highland, Claudia Schurmann, Anne E Justice, Rebecca S Fine, Jonathan P Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L Young, Tamuno Alfred, Mary F Feitosa, Nicholas G D Masca, Alisa K Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C Y Ng, Alex P Reiner, Sailaja Vedantam, Sara M Willems, Thomas W Winkler, Gonçalo Abecasis, Katja K Aben, Dewan S Alam, Sameer E Alharthi, Matthew Allison, Philippe Amouyel, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Lia E Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A Böger, Jette Bork-Jensen, Michiel L Bots, Erwin P Bottinger, Donald W Bowden, Ivan Brandslund, Gerome Breen, Murray H Brilliant, Linda Broer, Marco Brumat, Amber A Burt, Adam S Butterworth, Peter T Campbell, Stefania Cappellani, David J Carey, Eulalia Catamo, Mark J Caulfield, John C Chambers, Daniel I Chasman, Yii-Der I Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, Massimiliano Cocca, Francis S Collins, James P Cook, Janie Corley, Jordi Corominas Galbany, Amanda J Cox, David S Crosslin, Gabriel Cuellar-Partida, Angela D'Eustacchio, John Danesh, Gail Davies, Paul I W Bakker, Mark C H Groot, Renée Mutsert, Ian J Deary, George Dedoussis, Ellen W Demerath, Martin Heijer, Anneke I Hollander, Hester M Ruijter, Joe G Dennis, Josh C Denny, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Marie-Pierre Dubé, Alison M Dunning, Douglas F Easton, Todd L Edwards, David Ellinghaus, Patrick T Ellinor, Paul Elliott, Evangelos Evangelou, Aliki-Eleni Farmaki, I Sadaf Farooqi, Jessica D Faul, Sascha Fauser, Shuang Feng, Ele Ferrannini, Jean Ferrieres, Jose C Florez, Ian Ford, Myriam Fornage, Oscar H Franco, Andre Franke, Paul W Franks, Nele Friedrich, Ruth Frikke-Schmidt, Tessel E Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Jane Gibson, Vilmantas Giedraitis, Anette P Gjesing, Penny Gordon-Larsen, Mathias Gorski, Hans-Jörgen Grabe, Struan F A Grant, Niels Grarup, Helen L Griffiths, Megan L Grove, Vilmundur Gudnason, Stefan Gustafsson, Jeff Haessler, Hakon Hakonarson, Anke R Hammerschlag, Torben Hansen, Kathleen Mullan Harris, Tamara B Harris, Andrew T Hattersley, Christian T Have, Caroline Hayward, Liang He, Nancy L Heard-Costa, Andrew C Heath, Iris M Heid, Øyvind Helgeland, Jussi Hernesniemi, Alex W Hewitt, Oddgeir L Holmen, G Kees Hovingh, Joanna M M Howson, Yao Hu, Paul L Huang, Jennifer E Huffman, M Arfan Ikram, Erik Ingelsson, Anne U Jackson, Jan-Håkan Jansson, Gail P Jarvik, Gorm B Jensen, Yucheng Jia, Stefan Johansson, Marit E Jørgensen, Torben Jørgensen, J Wouter Jukema, Bratati Kahali, René S Kahn, Mika Kähönen, Pia R Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon L R Kardia, Fredrik Karpe, Sekar Kathiresan, Frank Kee, Lambertus A Kiemeney, Eric Kim, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S Kooner, Charles Kooperberg, Tellervo Korhonen, Peter Kovacs, Helena Kuivaniemi, Zoltán Kutalik, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A Lakka, David Lamparter, Ethan M Lange, Leslie A Lange, Claudia Langenberg, Eric B Larson, Nanette R Lee, Terho Lehtimäki, Cora E Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Honghuang Lin, Keng-Hung Lin, Li-An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Dajiang J Liu, Yongmei Liu, Ken S Lo, Artitaya Lophatananon, Andrew J Lotery, Anu Loukola, Jian'an Luan, Steven A Lubitz, Leo-Pekka Lyytikäinen, Satu Männistö, Gaëlle Marenne, Angela L Mazul, Mark I McCarthy, Roberta McKean-Cowdin, Sarah E Medland, Karina Meidtner, Lili Milani, Vanisha Mistry, Paul Mitchell, Karen L Mohlke, Leena Moilanen, Marie Moitry, Grant W Montgomery, Dennis O Mook-Kanamori, Carmel Moore, Trevor A Mori, Andrew D Morris, Andrew P Morris, Martina Müller-Nurasyid, Patricia B Munroe, Mike A Nalls, Narisu Narisu, Christopher P Nelson, Matt Neville, Sune F Nielsen, Kjell Nikus, Pål R Njølstad, Børge G Nordestgaard, Dale R Nyholt, Jeffrey R O'Connel, Michelle L O'Donoghue, Loes M Olde Loohuis, Roel A Ophoff, Katharine R Owen, Chris J Packard, Sandosh Padmanabhan, Colin N A Palmer, Nicholette D Palmer, Gerard Pasterkamp, Aniruddh P Patel, Alison Pattie, Oluf Pedersen, Peggy L Peissig, Gina M Peloso, Craig E Pennell, Markus Perola, James A Perry, John R B Perry, Tune H Pers, Thomas N Person, Annette Peters, Eva R B Petersen, Patricia A Peyser, Ailith Pirie, Ozren Polasek, Tinca J Polderman, Hannu Puolijoki, Olli T Raitakari, Asif Rasheed, Rainer Rauramaa, Dermot F Reilly, Frida Renström, Myriam Rheinberger, Paul M Ridker, John D Rioux, Manuel A Rivas, David J Roberts, Neil R Robertson, Antonietta Robino, Olov Rolandsson, Igor Rudan, Katherine S Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Yadav Sapkota, Naveed Sattar, Robert E Schoen, Pamela J Schreiner, Matthias B Schulze, Robert A Scott, Marcelo P Segura-Lepe, Svati H Shah, Wayne H-H Sheu, Xueling Sim, Andrew J Slater, Kerrin S Small, Albert V Smith, Lorraine Southam, Timothy D Spector, Elizabeth K Speliotes, John M Starr, Kari Stefansson, Valgerdur Steinthorsdottir, Kathleen E Stirrups, Konstantin Strauch, Heather M Stringham, Michael Stumvoll, Liang Sun, Praveen Surendran, Amy J Swift, Hayato Tada, Katherine E Tansey, Jean-Claude Tardif, Kent D Taylor, Alexander Teumer, Deborah J Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Betina H Thuesen, Anke Tönjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Jonathan P Tyrer, Rudolf Uher, André G Uitterlinden, Matti Uusitupa, Sander W Laan, Cornelia M Duijn, Nienke Leeuwen, Jessica van Setten, Mauno Vanhala, Anette Varbo, Tibor V Varga, Rohit Varma, Digna R Velez Edwards, Sita H Vermeulen, Giovanni Veronesi, Henrik Vestergaard, Veronique Vitart, Thomas F Vogt, Uwe Völker, Dragana Vuckovic, Lynne E Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A Wang, Shuai Wang, Yiqin Wang, Erin B Ware, Nicholas J Wareham, Helen R Warren, Dawn M Waterworth, Jennifer Wessel, Harvey D White, Cristen J Willer, James G Wilson, Daniel R Witte, Andrew R Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Pang Yao, Laura M Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, Wei Zhou, Krina T Zondervan, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Jerome I Rotter, John A Pospisilik, Fernando Rivadeneira, Ingrid B Borecki, Panos Deloukas, Timothy M Frayling, Guillaume Lettre, Kari E North, Cecilia M Lindgren, Joel N Hirschhorn, Ruth J F Loos Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding var Show more

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

📄 PDF DOI: 10.1038/s41588-017-0011-x

GIPR

Overexpression of melanocortin 2 receptor accessory protein 2 (MRAP2) in adult paraventricular MC4R neurons regulates energy intake and expenditure.

Giuseppe Bruschetta, Jung Dae Kim, Sabrina Diano +1 more · 2018 · Molecular metabolism · Elsevier · added 2026-04-24

Giuseppe Bruschetta, Jung Dae Kim, Sabrina Diano, Li F Chan Show less

Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons resp Show more

Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2. To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice. We assessed energy homeostasis, glucose metabolism, core body temperature, and response to MC3R/MC4R agonist MTII. Mc4r-cre Our data indicate a site-specific role for MRAP2 in PVN MC4R-expressing neurons in potentiating MC4R neuronal activation at baseline conditions in the regulation of food intake and energy expenditure. Show less

📄 PDF DOI: 10.1016/j.molmet.2018.09.010

MC4R

Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor.

Ye Ran Yoon, Tae-Gul Lee, Mi-Hyun Choi +6 more · 2018 · Experimental & molecular medicine · Nature · added 2026-04-24

Ye Ran Yoon, Tae-Gul Lee, Mi-Hyun Choi, Seung Woo Shin, Young-Gyu Ko, Im Joo Rhyu, Dong-Hoon Kim, Je Kyung Seong, Ja-Hyun Baik Show less

The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interactin Show more

The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling. Show less

📄 PDF DOI: 10.1038/s12276-018-0144-8

MC4R

Genetic Fine-Mapping and Identification of Candidate Genes and Variants for Adiposity Traits in Outbred Rats.

Gregory R Keele, Jeremy W Prokop, Hong He +19 more · 2018 · Obesity (Silver Spring, Md.) · Wiley · added 2026-04-24

Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, outbred heterogeneous Show more

Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, outbred heterogeneous stock (HS) rats were used in controlled environmental conditions to fine-map novel genetic modifiers of adiposity. Body weight and visceral fat pad weights were measured in male HS rats that were also genotyped genome-wide. Quantitative trait loci (QTL) were identified by genome-wide association of imputed single-nucleotide polymorphism (SNP) genotypes using a linear mixed effect model that accounts for unequal relatedness between the HS rats. Candidate genes were assessed by protein modeling and mediation analysis of expression for coding and noncoding variants, respectively. HS rats exhibited large variation in adiposity traits, which were highly heritable and correlated with metabolic health. Fine-mapping of fat pad weight and body weight revealed three QTL and prioritized five candidate genes. Fat pad weight was associated with missense SNPs in Adcy3 and Prlhr and altered expression of Krtcap3 and Slc30a3, whereas Grid2 was identified as a candidate within the body weight locus. These data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits. Show less

📄 PDF DOI: 10.1002/oby.22075

ADCY3

👤 Seung Chul Kim