Genes Regulating Lipid Metabolism Research Articles

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.

Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response.

The severe combined immunodeficiency disorder (SCID)-beige/albumin (Alb)-urokinase plasminogen activator (uPA) mouse containing a human-mouse chimeric liver is currently the only small animal model capable of supporting hepatitis C virus (HCV) infection. This model was utilized to characterize the host transcriptional response to HCV infection. The purpose of these studies was to investigate the genetic component of the host response to HCV infection and also to distinguish virus-induced gene expression changes from adaptive HCV-specific immune-mediated effects. Gene expression profiles from HCV-infected mice were also compared to those from HCV-infected patients. Analyses of the gene expression data demonstrate that host factors regulate the response to HCV infection, including the nature of the innate antiviral immune response. They also indicate that HCV mediates gene expression changes, including regulation of lipid metabolism genes, which have the potential to be directly cytopathic, indicating that liver pathology may not be exclusively mediated by HCV-specific adaptive immune responses. This effect appears to be inversely related to the activation of the innate antiviral immune response. In summary, the nature of the initial interferon response to HCV infection may determine the extent of viral-mediated effects on host gene expression.

Regulation of Lipid Metabolism Genes, Lipid Carrier Protein Lipophorin, and Its Receptor during Immune Challenge in the Mosquito Aedes aegypti

In the mosquito Aedes aegypti, the expression of two fat body genes involved in lipid metabolism, a lipid carrier protein lipophorin (Lp) and its lipophorin receptor (LpRfb), was significantly increased after infections with Gram (+) bacteria and fungi, but not with Gram (-) bacteria. The expression of these genes was enhanced after the infection with Plasmodium gallinaceum. RNA interference (RNAi) knockdown of Lp strongly restricted the development of Plasmodium oocysts, reducing their number by 90%. In Vg-DeltaREL1-A transgenic mosquitoes, with gain-of-function phenotype of Toll/REL1 immune pathway activated after blood feeding, both the Lp and LpRfb genes were overexpressed independently of septic injury. The same phenotype was observed in the mosquitoes with RNAi knockdown of Cactus, an IkappaB inhibitor in the Toll/REL1 pathway. These results showed that, in the mosquito fat body, both Lp and LpRfb gene expression were regulated by the Toll/REL1 pathway during immune induction by pathogen and parasite infections. Indeed, the proximal region of the LpRfb promoter contained closely linked binding motifs for GATA and NF-kappaB transcription factors. Transfection and in vivo RNAi knockdown experiments showed that the bindings of both GATA and NF-kappaB transcription factors to the corresponding motif were required for the induction of the LpRfb gene. These findings suggest that lipid metabolism is involved in the mosquito systemic immune responses to pathogens and parasites.

TEAVIGOTM (Epigallocatechin Gallate) Supplementation Prevents Obesity in Rodents by Reducing Adipose Tissue Mass

Background: This study investigated the antiobesity effects of TEAVIGO^TM, a product providing the most abundant green tea catechin, epigallocatechin gallate (EGCG), in a pure form. Two models of diet-induced obesity and an in vitro adipocyte differentiation assay were employed. Methods: Prevention and regression of diet-induced obesity by dietary supplementation with EGCG was studied in C57BL/6J mice and Sprague-Dawley rats, respectively. Expression of genes regulating lipid metabolism was assessed in adipose tissue. The effects of EGCG on adipocyte differentiation were investigated in vitro. Results: In C57BL/6J mice, EGCG supplementation prevented diet-induced increases in body weight and in fed state plasma levels of glucose, triglycerides, and leptin. EGCG decreased subcutaneous and epididymal adipose tissue weights. Supplementation of EGCG reversed the established obesity in Sprague-Dawley rats. Fatty acid synthase and acetyl-CoA carboxylase-1 mRNA levels were markedly decreased in adipose tissue of EGCG-supplemented mice. EGCG dose dependently inhibited adipocyte differentiation in vitro. Conclusion: This study shows for the first time that supplementation with the most abundant green tea polyphenol, EGCG, abolishes diet-induced obesity. This effect is at least partly mediated via a direct influence on adipose tissue. Thus, dietary supplementation with EGCG should be considered as a valuable natural treatment option for obesity.

Human skeletal muscle PPARα expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key regulator of fatty acid oxidation in skeletal muscle, but few data exist from humans in vivo. To investigate whether insulin sensitivity in skeletal muscle and body mass index (BMI) were associated with skeletal muscle expression of PPARalpha and with important genes regulating lipid metabolism in humans in vivo, we undertook hyperinsulinemic-euglycemic clamps and measured PPARalpha mRNA levels and mRNA levels of lipid regulating PPARalpha response genes in skeletal muscle biopsies. mRNA levels were measured in 16 men, using a novel highly sensitive and specific medium throughput quantitative competitive PCR that allows reproducible measurement of multiple candidate mRNAs simultaneously. mRNA levels of PPARalpha were positively correlated with mRNA levels of CD36 (r = 0.77, P = 0.001), lipoprotein lipase (r = 0.54, P = 0.024), muscle-type carnitine palmitoyltransferase-I (r = 0.54, P = 0.024), uncoupling protein-2 (r = 0.63, P = 0.008), and uncoupling protein-3 (r = 0.53, P = 0.026), but not with measures of insulin sensitivity, BMI, or GLUT4, which plays an important role in insulin-mediated glucose uptake. Thus our data suggest that in humans skeletal muscle PPARalpha expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPARalpha expression in skeletal muscle.

Hepatic expression of genes regulating lipid metabolism in rabbits.

The liver plays a central role in lipid metabolism and plasma lipoprotein homeostasis. This dynamic process is regulated by a variety of liver-derived proteins. However, the specific liver cells that express these proteins are largely unknown. In the current study we measured mRNA levels for 13 genes encoding proteins involved in lipid metabolism in isolated rabbit hepatic parenchymal and nonparenchymal cells. For these analyses we cloned partial rabbit cDNAs for apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), apolipoprotein E (apoE), cholesteryl ester transfer protein (CETP), hepatic lipase (HL), lipoprotein lipase (LPL), HMG-CoA reductase, LDL-receptor, 7 alpha-hydroxylase, albumin, bile salt-dependent cholesteryl ester hydrolase (CEH), lecithin:cholesterol acyl transferase (LCAT), and plasminogen activator inhibitor protein-1 (PAI-1). The cDNAs provided the basis for developing quantitative RNAse protection assays for each mRNA. These assays were used to determine whether differential patterns of mRNA expression existed between liver and other tissues and between hepatic parenchymal and nonparenchymal cells. The data demonstrate a diverse range in tissue distribution and mRNA abundance. Liver expressed all mRNAs except for LPL and CEH. Messenger RNA levels in isolated liver cell populations normalized to total RNA revealed a cell segregation pattern for hepatic gene expression: parenchymal cells showed higher levels of apoA-I, apoB, apoE, albumin, LCAT, HL, and 7 alpha-hydroxylase mRNAs compared to nonparenchymal cells while nonparenchymal cells showed higher levels of CETP, LDL-receptor, HMG-CoA reductase, and PAI-1 mRNAs compared to parenchymal cells. These data demonstrate the existence of differential mRNA expression patterns in rabbit liver cell populations for genes encoding proteins affecting lipid metabolism.