👤 Alireza Khadem

Recent studies suggest a link between dietary fat quality and obesity. Genetic risk scores (GRS) can predict obesity risk based on genetic factors. This study investigates how GRS and fatty acid quality affect visceral adiposity index (VAI) and body adiposity index (BAI) in overweight and obese women. In this study, 278 overweight and obese women (aged 18-58) participated. We have used a comprehensive food frequency questionnaire (FFQ) to evaluate dietary intake and the fatty acids quality indexes. We have employed standard methods to measure biochemical factors, anthropometrics, and physical activity levels. Finally, the GRS was created by combining three SNPs [CAV-1 (rs3807992), Cry-1 (rs2287161), and MC4R (rs17782313)]. The study found that there was no significant association between the quality of fat intake (as measured by CSI score and N6/N3 score) and VAI or BAI in both crude (B = 70.70, SE = 35.14, CI:1.81-139.55, P = 0.04) and adjusted models (B = 93.67, SE = 39.28, CI:16.68-17.68, P = 0.01). CSI provides information on cholesterol and saturated fats. However, there was a notable interaction between the GRS and the N6/N3 score on VAI, suggesting that obese women with high obesity-related SNPs who consumed foods with a higher ratio of N6/N3 fatty acids tended to have an increased VAI. This study shows; that eating more food sources containing a higher ratio of N6/N3 may be the reason for the increase in VAI in obese women who have high obesity-related SNPs and emphasizes the matter of personalized nutrition in obesity issues. Show less

The aim of this study is to investigate the interaction of fatty acid quality indices and genes related to lipid homeostasis on mental health among overweight and obese women. This cross-sectional study included 279 overweight and obese women for N6/N3 ratio and 378 overweight and obese women for CSI aged 18-58 years. Mental health were evaluated using Depression Anxiety Stress Scales (DASS-21). The anthropometric indices, biochemical parameters, body composition and dietary fat quality were measured. MC4R (rs17782313) and Caveolin-1 (CAV-1) (rs3807992) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results of the study showed that after adjusting for age, energy intake, thyroid disease, physical activity, and BMI, a positive interaction between TC genotype of MC4R and CSI on depression (β = 0.39, CI = 0.12, 0.66, P = 0.004), and DASS-21 (β = 0.074, CI = 0.04, 1.44, P = 0.036). Also, there were a marginal significant interactions between AG genotype of CAV-1 and N6/N3 ratio on depression in adjustment model1 (β = 16.83, CI = - 0.19, 33.85, P = 0.053). Our findings showed that increasing adherence to fatty acid quality indices by considering genes related to lipid homeostasis was related to increasing depression in our population. Show less

The liver X receptor (LXR) and constitutive androstane receptor (CAR) are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. Here, we show that LXRα and CAR are functionally related in vivo. Loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation, whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. On the other hand, a combined loss of LXR α and β increased the basal expression of xenobiotic CAR target genes, whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXRα and CAR was also observed in cell culture and reporter gene assays. LXRα, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor coactivators. Interestingly, although CAR competed with LXRα for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXRα. In vivo chromatin immunoprecipitation assay showed that cotreatment of a CAR agonist compromised the LXR agonist responsive recruitment of LXRα to Srebp-1c, whereas an LXR agonist inhibited the CAR agonist-responsive recruitment of CAR to Cyp2b10. In conclusion, our results have revealed dual functions of LXRα and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis. Show less

Liver X receptor (LXR) is known to promote hepatic lipogenesis by activating the lipogenic transcriptional factor sterol regulatory element-binding protein (Srebp). Pregnane X receptor (PXR), a previously known "xenobiotic receptor," could mediate a Srebp-independent lipogenic pathway by activating the free fatty acid uptake transporter Cd36. The goal of this study is to investigate further the role of Cd36 in hepatic steatosis. Wild-type, LXR transgenic, PXR transgenic, and Cd36 null mice were used to study the regulation of Cd36 and other hepatic lipogenic genes and the implication of this regulation in hepatic steatosis. Promoter sequences of Cd36 and peroxisome proliferator-activated receptor (PPAR) gamma were cloned, and their respective regulation by LXR and PXR was investigated by combinations of receptor-DNA binding and reporter gene assays. We showed that genetic (transgene) or pharmacologic (ligands) activation of LXR induced Cd36. Promoter analysis established Cd36 as a novel transcription target of LXRalpha. Moreover, the hepatic steatosis induced by LXR agonists was largely abolished in Cd36 null mice. We also showed that PPARgamma, a positive regulator of Cd36, is a transcriptional target of PXR, suggesting that PXR can regulate Cd36 directly or through its activation of PPARgamma. Interestingly, both LXR-mediated Cd36 regulation and PXR-mediated PPARgamma regulation are liver specific. We conclude that Cd36 is a shared target of LXR, PXR, and PPARgamma. The network of CD36 regulation by LXR, PXR, and PPARgamma establishes this free fatty acid transporter as a common target of orphan nuclear receptors in their mediation of lipid homeostasis. Show less

The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating the oxysterol 7alpha-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the RORalpha null (RORalpha(sg/sg)) mice, suggesting RORalpha as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of RORalpha, and transfection of RORalpha induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be RORalpha-specific, because RORgamma had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by RORalpha was suppressed by LXRalpha (NR1H3), whereas RORalpha inhibited both the constitutive and ligand-dependent activities of LXRalpha. The mutual suppression between RORalpha and LXR was supported by the in vivo observation that loss of RORalpha increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR alpha and beta isoforms showed activation of selected RORalpha target genes. Our results have revealed a novel role for RORalpha and a functional interplay between RORalpha and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis. Show less