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Hepatic hepatocyte nuclear factor 4? is essential for maintaining triglyceride and cholesterol homeostasis.

ABSTRACT: Loss-of-function mutations in human hepatocyte nuclear factor 4? (HNF4?) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4? function on lipid homeostasis.We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4? (Ad-shHnf4?). Tail vain injection of C57BL/6J mice with Ad-shHnf4? reduced hepatic Hnf4? expression and resulted in striking phenotypes, including the development of fatty liver and a >80% decrease in plasma levels of triglycerides, total cholesterol, and high-density lipoprotein cholesterol. These latter changes were associated with reduced hepatic lipogenesis and impaired very-low-density lipoprotein secretion. Deficiency in hepatic Hnf4? did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, overexpression of Hnf4? induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4?-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4?. Because of selective gene regulation, mice overexpressing hepatic Hnf4? had unchanged plasma triglyceride levels and decreased plasma cholesterol levels.Loss of hepatic HNF4? results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4? activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4? is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.

SUBMITTER: Yin L

PROVIDER: S-EPMC3079249 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Hepatic hepatocyte nuclear factor 4α is essential for maintaining triglyceride and cholesterol homeostasis.

Yin Liya L Ma Huiyan H Ge Xuemei X Edwards Peter A PA Zhang Yanqiao Y

Arteriosclerosis, thrombosis, and vascular biology 20101111 2

<h4>Objective</h4>Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4α function on lipid homeostasis.<h4>Methods and results</h4>We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4α (Ad-shHnf4α). Tail vain ...[more]

PMID: 21071704

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Project description:AIM:To uncover the role of hepatocyte nuclear factor 4 alpha (HNF4?) in regulating hepatic expression of microRNAs. METHODS:Microarray and real-time PCR were used to determine hepatic expression of microRNAs in young-adult mice lacking Hnf4? expression in liver (Hnf4?-LivKO). Integrative genomics viewer software was used to analyze the public chromatin immunoprecipitation-sequencing datasets for DNA-binding of HNF4?, RNA polymerase-II, and histone modifications to loci of microRNAs in mouse liver and human hepatoma cells. Dual-luciferase reporter assay was conducted to determine effects of HNF4? on the promoters of mouse and human microRNAs as well as effects of microRNAs on the untranslated regions (3'UTR) of two genes in human hepatoma cells. RESULTS:Microarray data indicated that most microRNAs remained unaltered by Hnf4? deficiency in Hnf4?-LivKO mice. However, certain liver-predominant microRNAs were down-regulated similarly in young-adult male and female Hnf4?-LivKO mice. The down-regulation of miR-101, miR-192, miR-193a, miR-194, miR-215, miR-802, and miR-122 as well as induction of miR-34 and miR-29 in male Hnf4?-LivKO mice were confirmed by real-time PCR. Analysis of public chromatin immunoprecipitation-sequencing data indicates that HNF4? directly binds to the promoters of miR-101, miR-122, miR-194-2/miR-192 and miR-193, which is associated with histone marks of active transcription. Luciferase reporter assay showed that HNF4? markedly activated the promoters of mouse and human miR-101b/miR-101-2 and the miR-194/miR-192 cluster. Additionally, miR-192 and miR-194 significantly decreased activities of luciferase reporters for the 3'UTR of histone H3F3 and chromodomain helicase DNA binding protein 1 (CHD1), respectively, suggesting that miR-192 and miR-194 might be important in chromosome remodeling through directly targeting H3F3 and CHD1. CONCLUSION:HNF4? is essential for hepatic basal expression of a group of liver-enriched microRNAs, including miR-101, miR-192, miR-193a, miR-194 and miR-802, through which HNF4? may play a major role in the post-transcriptional regulation of gene expression and maintenance of the epigenome in liver.

Project description:Alcohol consumption is a major cause of fatty liver, and dietary saturated fats have been shown to protect against alcoholic fatty liver. This study investigated the mechanisms of how dietary saturated fat may modulate alcohol-induced hepatic lipid dyshomeostasis.Male Sprague Dawley rats were pair-fed with 3 isocaloric liquid diets, control, alcohol, and medium chain triglyceride (MCT)/alcohol, respectively, for 8 weeks. The control and alcohol diets were based on the Lieber-DeCarli liquid diet formula with 30% total calories derived from corn oil (rich in unsaturated long chain fatty acids). The corn oil was replaced by MCT, which consists of exclusive saturated fatty acids, in the MCT/alcohol diet. HepG2 cell culture was conducted to test the effects of unsaturated fatty acids on hepatocyte nuclear factor-4? (HNF4?) and the role of HNF4? in regulating hepatocyte lipid homeostasis.Alcohol feeding caused significant lipid accumulation, which was attenuated by dietary MCT. The major effect of alcohol on hepatic gene expression is the up-regulation of CYP4A1, CD36, and GPAT3, and down-regulation of apolipoprotein B (ApoB). Dietary MCT further up-regulated CYP4A1 gene, normalized ApoB gene, and up-regulated MTTP and SCD1 genes. The protein level of HNF4?, a master transcription factor of the liver, was reduced by alcohol feeding, which was normalized by dietary MCT. Fatty acid profiling demonstrated that alcohol feeding dramatically increased hepatic unsaturated long chain fatty acyl species, particularly linoleic acid and oleic acid, which was attenuated by dietary MCT. Dietary MCT attenuated alcohol-reduced serum triglyceride level and modulated the fatty acid composition of the serum triglycerides. Cell culture study demonstrated polyunsaturated linoleic acid rather than monounsaturated oleic acid inactivated HNF4? in HepG2 cells. Knockdown of HNF4? caused lipid accumulation in HepG2 cells due to dysregulation of very low density lipoprotein secretion.Results suggest that dietary MCT prevents alcohol-induced hepatic lipid accumulation, at least partially, through reducing hepatic polyunsaturated long chain fatty acids and preserving HNF4?.

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Hepatic hepatocyte nuclear factor 4? is essential for maintaining triglyceride and cholesterol homeostasis.

Publications

Hepatic hepatocyte nuclear factor 4α is essential for maintaining triglyceride and cholesterol homeostasis.

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