👤 Hyeung-Rak Kim

Biomarkers in exposure assessment are defined as the quantifiable targets that indicate the exposure to hazardous chemicals and their resulting health effect. In this study, we aimed to identify, validate, and characterize the mRNA biomarker that can detect the exposure of sodium cyanide. To identify reliable biomarkers for sodium cyanide exposure, critical criteria were defined for candidate selection: (1) the expression level of mRNA significantly changes in response to sodium thiocyanate treatment in transcriptomics results (fold change > 2.0 or <0.50, adjusted Show less

We investigated changes in rumen fermentation, peripheral blood metabolites and hormones, and hepatic transcriptomic dynamics in Holstein cows with and those without subacute ruminal acidosis (SARA) during the periparturient period. Sixteen multiparous Holstein cows were categorized in the SARA ( Show less

Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. Here, we conducted genome-wide association studies (GWASs) to identify the MUHNW and MHO genetic indices. The study dataset comprised genome-wide single-nucleotide polymorphism genotypes and epidemiological data from 49,915 subjects categorised into four phenotypes-metabolically healthy normal weight (MHNW), MUHNW, MHO, and metabolically unhealthy obese (MUHO). We conducted two GWASs using logistic regression analyses and adjustments for confounding variables (model 1: MHNW versus MUHNW and model 2: MHO versus MUHO). GCKR, ABCB11, CDKAL1, LPL, CDKN2B, NT5C2, APOA5, CETP, and APOC1 were associated with metabolically unhealthy phenotypes among normal weight individuals (model 1). LPL, APOA5, and CETP were associated with metabolically unhealthy phenotypes among obese individuals (model 2). The genes common to both models are related to lipid metabolism (LPL, APOA5, and CETP), and those associated with model 1 are related to insulin or glucose metabolism (GCKR, CDKAL1, and CDKN2B). This study reveals the genetic architecture of the MUHNW and MHO phenotypes in a Korean population-based cohort. These findings could help identify individuals at a high metabolic risk in normal weight and obese populations and provide potential novel targets for the management of metabolically unhealthy phenotypes. Show less

Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)-/- and ApoE-/-FXR-/- mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. Compared with ApoE-/- mice, ApoE-/-FXR-/- mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE-/-FXR-/- mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis. Show less

The plasma proteome of 51 non-metastatic breast cancer patients receiving neoadjuvant chemotherapy (NCT) was prospectively analyzed by high-resolution mass spectrometry coupled with nano-flow liquid chromatography using blood drawn at the time of diagnosis. Plasma proteins were identified as potential biomarkers, and their correlation with clinicopathological variables and survival outcomes was analyzed. Of 51 patients, 20 (39.2%) were HR+/HER2-, five (9.8%) were HR+/HER2+, five (9.8%) were HER2+, and 21 (41.2%) were triple-negative subtype. During a median follow-up of 52.0 months, there were 15 relapses (29.4%) and eight deaths (15.7%). Four potential biomarkers were identified among differentially expressed proteins: APOC3 had higher plasma concentrations in the pathological complete response (pCR) group, whereas MBL2, ENG, and P4HB were higher in the non-pCR group. Proteins statistically significantly associated with survival and capable of differentiating low- and high-risk groups were MBL2 and P4HB for disease-free survival, P4HB for overall survival, and MBL2 for distant metastasis-free survival (DMFS). In the multivariate analysis, only MBL2 was a consistent risk factor for DMFS (HR: 9.65, 95% CI 2.10-44.31). The results demonstrate that the proteomes from non-invasive sampling correlate with pCR and survival in breast cancer patients receiving NCT. Further investigation may clarify the role of these proteins in predicting prognosis and thus their therapeutic potential for the prevention of recurrence. Show less

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with Show less

Depression is a common symptom of many mental disorders, especially major depressive disorder (MDD) and bipolar disorder (BD). Previous studies have reported that these diseases share common pathophysiological pathways; therefore, this study elucidated whether the plasma levels of protein markers related to common depressive symptoms differed between patients with BD and those with MDD. Plasma samples of 71 patients with mood disorders and clinical manifestations were analyzed in this study. After depleting the abundant proteins, liquid chromatography-tandem mass spectrometry and label-free quantification were performed. Five proteins, viz., cholesteryl ester transfer protein (CETP), apolipoprotein D (APOD), mannan-binding lectin serine protease 2 (MASP2), Ig lambda chain V-II region BO (IGLV2-8) and Ig kappa chain V-III region NG9 (IGKV3-20) were negatively associated with the total scores of the Hamilton depression rating scale (HAM-D), after adjusting for the covariates. CETP and APOD also showed significant negative correlations with the anhedonia/retardation and guilt/agitation scores of the HAM-D. Four proteins, namely, Ig kappa chain V-II region TEW (IGKC; IGKV2D-28), Ig lambda variable 5-45 (IGLV5-45), complement factor H (CFH) and attractin (ATRN), showed significant associations with anhedonia/retardation after adjusting for covariates. Proteins that significantly correlated with the symptoms could predict the remission state of depression (area under the curve [AUC], 0.83) and anhedonia/retardation (AUC, 0.80). Bioinformatics analysis revealed that complement activation, immune response, and lipid metabolism were significantly enriched pathways. Although our study design was cross-sectional and no controls were included, protein markers identified in this preliminary study will be further investigated in our subsequent longitudinal study. Show less

After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites. These in turn, infect red blood cells and cause malaria symptoms. To initiate a productive infection, sporozoites must exit the circulation by traversing the blood lining of the liver vessels after which they infect hepatocytes with unique specificity. We screened a phage display library for peptides that structurally mimic (mimotope) a sporozoite ligand for hepatocyte recognition. We identified HP1 (hepatocyte-binding peptide 1) that mimics a ~50 kDa sporozoite ligand (identified as phospholipid scramblase). Further, we show that HP1 interacts with a ~160 kDa hepatocyte membrane putative receptor (identified as carbamoyl-phosphate synthetase 1). Importantly, immunization of mice with the HP1 peptide partially protects them from infection by the rodent parasite P. berghei. Moreover, an antibody to the HP1 mimotope inhibits human parasite P. falciparum infection of human hepatocytes in culture. The sporozoite ligand for hepatocyte invasion is a potential novel pre-erythrocytic vaccine candidate. Show less

Immunohistochemical (IHC) assays for programmed death ligand 1 (PD-L1) expression are crucial for guiding immune checkpoint inhibitor therapies in advanced gastric adenocarcinoma (AGC). The results from clinical trials of various PD-L1 antibody clones are variable and the exchangeability of these assays is a highly sought goal. The aim of this study was to determine whether three different PD-L1 assays (SP263 and 22C3 on the Dako and Ventana platforms) are interchangeable through analysis of their concordance rate within samples between biopsy and paired resected specimens. One hundred pairs of biopsied and resected AGC specimens were collected and stained for PD-L1. The combined positive score (CPS) was used for the IHC analysis and a four tiered system was applied, i.e., <1, 1 to < 5, 5 to 50, and >50. The agreement for the different IHC assays was low across all cut-offs with the biopsied or resected specimens (biopsy, κ=0.17-0.453; resection, κ=0.02-0.311). The overall positive agreement (OPA) for the PD-L1 results from the biopsy and resection tissues was 100% (SP263, κ=1), 86% (22C3 on the Dako platform, κ=0.693) and 93% (22C3 on the Ventana platform, κ=0.82) at the CPS1 cut-off. The low concordances among the three PD-L1 IHC assays indicated that they cannot be used interchangeably in clinical practice. The results of the SP263 assay using CPS1 showed the highest agreement between the biopsy and resection specimens, suggesting SP263 may provide the most representative approach for the evaluation of PD-L1 status in gastric cancer. Show less

RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer. Show less

Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, dysregulation of the thymic selection process often leads to autoimmunity. Here, we show that Capicua (CIC), a transcriptional repressor that suppresses autoimmunity, controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impairs both positive and negative selection of thymocytes. CIC deficiency attenuated TCR signaling in CD4 Show less

Inhibitors of tropomyosin-related kinases (TRKs) display remarkable outcomes in the regression of cancers harboring the Neurotrophin Receptors Tyrosine Kinase (NTRK) fusion gene. As a result, TRKs have become attractive targets in anti-cancer drug discovery programs. Here, we demonstrate that AZD4547, a highly potent and selective inhibitor of fibroblast growth factor receptor (FGFR), displays anti-tumor activity against KM12(Luc) harboring the TPM3-NTRK1 fusion gene associated with its direct inhibition of TRKs. The results of profiling, using a 64-member in-house cancer cell panel, show that AZD4547 displays anti-proliferation activity against KM12(Luc) with a GI Show less

Communication and teamwork are essential during inpatient emergencies such as cardiac arrest and rapid response (RR) codes. We investigated whether wearing numbered jerseys affect directed commands, teamwork, and performance during simulated codes. Eight teams of 6 residents participated in 64 simulations. Four teams were randomized to the experimental group wearing numbered jerseys, and four to the control group wearing work attire. The experimental group used more directed commands (49% vs. 31%, p < .001) and had higher teamwork score (25 vs. 18, p < .001) compared with control group. There was no difference in time to initiation of chest compression, bag-valve-mask ventilation, and correct medications. Time to defibrillation was longer in the experimental group (190 vs. 140 seconds, p = .035). Using numbered jerseys during simulations was associated with increased use of directed commands and better teamwork. Time to performance of clinical actions was similar except for longer time to defibrillation in the jersey group. Show less

Like humans, weight control in overweight dogs is associated with a longer life expectancy and a healthier life. Dietary supplements are one of the best strategies for controlling obesity and obesity-associated diseases. This study was conducted to assess the potential of black ginseng (BG) and silkworm (SW) as supplements for weight control in diet-induced overweight beagle dogs. To investigate the changes that occur in dogs administered the supplements, different obesity-related parameters, such as body condition score (BCS), blood fatty acid profile, transcriptome, and microbiome, were assessed in high energy diet (HD) and HD with BG + SW supplementation (HDT) groups of test animals. After 12 weeks of BG + SW supplementation, total cholesterol and triglyceride levels were reduced in the HDT group. In the transcriptome analysis, nine genes (NUGGC, EFR3B, RTP4, ACAN, HOXC4, IL17RB, SOX13, SLC18A2, and SOX4) that are known to be associated with obesity were found to be differentially expressed between the ND (normal diet) and HD groups as well as the HD and HDT groups. Significant changes in some taxa were observed between the HD and ND groups. These data suggest that the BG + SW supplement could be developed as dietary interventions against diet-induced obesity, and obesity-related differential genes could be important candidates in the mechanism of the anti-obesity effects of the BG + SW supplement. Show less

Skeletal dysplasia (SD), a heterogeneous disease group with rare incidence and various clinical manifestations, is associated with multiple causative genes. For clinicians, accurate diagnosis of SD is clinically and genetically difficult. The development of next-generation sequencing (NGS) has substantially aided in the genetic diagnosis of SD. In this study, we conducted a targeted NGS of 437 genes - included in the nosology of SD published in 2019 - in 31 patients with a suspected SD. The clinical and genetic diagnoses were confirmed in 16 out of the 31 patients, and the diagnostic yield was 51.9%. In these patients, 18 pathogenic variants were found in 13 genes ( Show less

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in Show less

Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity. Show less

Plasticity in fatty acid metabolism is increasingly recognized as a major feature influencing cancer progression and efficacy of treatments. Estrogen receptor positive MCF7 human breast cancer cells have long been known to have no FADS2-mediated Δ6-desaturase activity. Our objective was to examine the effect of estrogen and the "antiestrogen" aromatase inhibitor letrozole, on Δ5- and Δ6-desaturase synthesized fatty acids in vitro. Eicosa-11,14-dienoic acid (20:2n-6), a known substrate for both FADS1 and FADS2, was used as a sentinel of relative FADS2 and FADS1 activity. MCF7 cells and four additional estrogen responsive wild type cell lines (HepG2, SK-N-SH, Y79 and Caco2) were studied. FAME were quantified by GC-FID and structures identified by GCCACI-MS/MS. In all five cell lines, estrogen caused a dose dependent decrease in sciadonic acid (5,11,14-20:3, ScA) via apparent inhibition of FADS1 activity, and had no effect on FADS2 catalyzed synthesis of dihomo-gamma linolenic acid (8,11,14-20:3; DGLA). In MCF7 cells, letrozole caused a dose dependent increase in FADS2-catalyzed DGLA synthesis, which plateaued in SK-N-SH cells. Letrozole restores Δ6-desaturase mediated synthesis of the anti-inflammatory PGE1-precursor DGLA in vitro and is the first endocrine-active agent to have opposing effects on FADS1 and FADS2 catalyzed activities. Show less

Glucocorticoids are a highly effective first-line treatment option for many inflammatory diseases, including asthma. Some patients develop a steroid-resistant condition, yet, the cellular and molecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3 Show less

Over the years, interleukin (IL)-27 has received much attention because of its highly divergent, sometimes even opposing, functions in immunity. IL-30, the p28 subunit that forms IL-27 together with Ebi3 and is also known as IL-27p28 or IL-27A, has been considered a surrogate to represent IL-27. However, it was later discovered that IL-30 can form complexes with other protein subunits, potentially leading to overlapping or discrete functions. Furthermore, there is emerging evidence that IL-30 itself may perform immunomodulatory functions independent of Ebi3 or other binding partners and that IL-30 production is strongly associated with certain cancers in humans. In this review, we will discuss the biology of IL-30 and other IL-30-associated cytokines and their functions in inflammation and cancer. Show less

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR-positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy. Show less

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive ( Show less

Williams syndrome (WS) is a relatively rare microdeletion disorder that occurs in as many as 1:7,500 individuals. WS arises due to the mispairing of low-copy DNA repetitive elements at meiosis. The deletion size is similar across most individuals with WS and leads to the loss of one copy of 25-27 genes on chromosome 7q11.23. The resulting unique disorder affects multiple systems, with cardinal features including but not limited to cardiovascular disease (characteristically stenosis of the great arteries and most notably supravalvar aortic stenosis), a distinctive craniofacial appearance, and a specific cognitive and behavioural profile that includes intellectual disability and hypersociability. Genotype-phenotype evidence is strongest for ELN, the gene encoding elastin, which is responsible for the vascular and connective tissue features of WS, and for the transcription factor genes GTF2I and GTF2IRD1, which are known to affect intellectual ability, social functioning and anxiety. Mounting evidence also ascribes phenotypic consequences to the deletion of BAZ1B, LIMK1, STX1A and MLXIPL, but more work is needed to understand the mechanism by which these deletions contribute to clinical outcomes. The age of diagnosis has fallen in regions of the world where technological advances, such as chromosomal microarray, enable clinicians to make the diagnosis of WS without formally suspecting it, allowing earlier intervention by medical and developmental specialists. Phenotypic variability is considerable for all cardinal features of WS but the specific sources of this variability remain unknown. Further investigation to identify the factors responsible for these differences may lead to mechanism-based rather than symptom-based therapies and should therefore be a high research priority. Show less

Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway. Show less

Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases. Show less

Fat accumulation results from increased fat absorption and/or defective fat metabolism. Currently, the lipid-sensing nuclear receptor that controls fat utilization in hepatocytes is elusive. Liver X receptor alpha (LXRα) promotes accumulation of lipids through the induction of several lipogenic genes. However, its effect on lipid degradation is open for study. Here, we investigated the inhibitory role of LXRα in autophagy/lipophagy in hepatocytes and the underlying basis. In LXRα knockout mice fed a high-fat diet, or cell models, LXRα activation suppressed the function of mitochondria by inhibiting autophagy/lipophagy and induced hepatic steatosis. Gene sets associated with "autophagy" were enriched in hepatic transcriptome data. Autophagy flux was markedly augmented in the LXRα knockout mouse liver and primary hepatocytes. Mechanistically, LXRα suppressed autophagy-related 4B cysteine peptidase (ATG4B) and Rab-8B, responsible for autophagosome and -lysosome formation, by inducing let-7a and microRNA (miR)-34a. Chromatin immunoprecipitation assay enabled us to find LXRα as a transcription factor of let-7a and miR-34a. Moreover, 3' untranslated region luciferase assay substantiated the direct inhibitory effects of let-7a and miR-34a on ATG4B and Rab-8B. Consistently, either LXRα activation or the let-7a/miR-34a transfection lowered mitochondrial oxygen consumption rate and mitochondrial transmembrane potential and increased fat levels. In obese animals or nonalcoholic fatty liver disease (NAFLD) patients, let-7a and miR-34a levels were elevated with simultaneous decreases in ATG4B and Rab-8B levels. LXRα inhibits autophagy in hepatocytes through down-regulating ATG4B and Rab-8B by transcriptionally activating microRNA let-7a-2 and microRNA 34a genes and suppresses mitochondrial biogenesis and fuel consumption. This highlights a function of LXRα that culminates in the progression of liver steatosis and steatohepatitis, and the identified targets may be applied for a therapeutic strategy in the treatment of NAFLD. Show less

Ventral subiculum (vSUB) is integral to the regulation of stress and reward; however, the intrinsic connectivity and synaptic properties of the inhibitory local circuit are poorly understood. Neurexin-3 (Nrxn3) is highly expressed in hippocampal inhibitory neurons, but its function at inhibitory synapses has remained elusive. Using slice electrophysiology, imaging, and single-cell RNA sequencing, we identify multiple roles for Nrxn3 at GABAergic parvalbumin (PV) interneuron synapses made onto vSUB regular-spiking (RS) and burst-spiking (BS) principal neurons. Surprisingly, we find that intrinsic connectivity of vSUB and synaptic function of Nrxn3 in vSUB are sexually dimorphic. We reveal that PVs make preferential contact with RS neurons in male mice, but BS neurons in female mice. Furthermore, we determine that despite comparable Nrxn3 isoform expression in male and female PV neurons, Nrxn3 knockout impairs synapse density, postsynaptic strength, and inhibitory postsynaptic current (IPSC) amplitude at PV-RS synapses in males, but enhances presynaptic release and IPSC amplitude in females. Show less