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

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

Yin Liya; Ma Huiyan; Ge Xuemei; Edwards Peter A; Zhang Yanqiao

Arteriosclerosis, thrombosis, and vascular biology

2011

2011-02

OBJECTIVE: Loss-of-function mutations in human hepatocyte nuclear factor 4alpha (HNF4alpha) 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 HNF4alpha function on lipid homeostasis. METHODS AND RESULTS: We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4alpha (Ad-shHnf4alpha). Tail vain injection of C57BL/6J mice with Ad-shHnf4alpha reduced hepatic Hnf4alpha expression and resulted in striking phenotypes, including the development of fatty liver and a \textgreater80% 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 Hnf4alpha 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 Hnf4alpha induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4alpha-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4alpha. Because of selective gene regulation, mice overexpressing hepatic Hnf4alpha had unchanged plasma triglyceride levels and decreased plasma cholesterol levels. CONCLUSIONS: Loss of hepatic HNF4alpha results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4alpha activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4alpha is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.

Adenoviridae/genetics; Animal; Animals; Cells; Cholesterol; Cholesterol/*metabolism; Cultured; Fatty Liver/metabolism/physiopathology; HDL/metabolism; Hepatocyte Nuclear Factor 4/drug effects/genetics/*physiology; Hepatocytes/cytology/*metabolism; Homeostasis/genetics/*physiology; Inbred C57BL; Lipid Metabolism/genetics/physiology; Mice; Models; RNA; Small Interfering/genetics/pharmacology; Triglycerides/*metabolism; VLDL/metabolism

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

328–336

2

31