Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 12, Pages 3891-3905Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011487
Keywords
vitamin D; nuclear receptor; liver metabolism; lipid metabolism; insulin resistance; gene regulation; hepatic steatosis; hepatocyte nuclear factor 4? (HNF4?); metabolic syndrome; nonalcoholic fatty liver disease (NAFLD)
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Funding
- National Key R&D Program of China [2017YFC0908900, 2018YFA0109800]
- National Natural Science Foundation of China [81570523, 81700485, 81722009, 81770573, U180321]
- Key Research and Development Program of Zhejiang Province Grant [2020C03033]
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Epidemiological studies have suggested a link between vitamin D deficiency and increased risk for nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms have remained unclear. Here, using both clinical samples and experimental rodent models along with several biochemical approaches, we explored the specific effects and mechanisms of vitamin D deficiency in NAFLD pathology. Serum vitamin D levels were significantly lower in individuals with NAFLD and in high-fat diet (HFD)-fed mice than in healthy controls and chow-fed mice, respectively. Vitamin D supplementation ameliorated HFD-induced hepatic steatosis and insulin resistance in mice. Hepatic expression of vitamin D receptor (VDR) was up-regulated in three models of NAFLD, including HFD-fed mice, methionine/choline-deficient diet (MCD)-fed mice, and genetically obese (ob/ob) mice. Liver-specific VDR deletion significantly exacerbated HFD- or MCD-induced hepatic steatosis and insulin resistance and also diminished the protective effect of vitamin D supplementation on NAFLD. Mechanistic experiments revealed that VDR interacted with hepatocyte nuclear factor 4 ? (HNF4?) and that overexpression of HNF4? improved HFD-induced NAFLD and metabolic abnormalities in liver-specific VDR-knockout mice. These results suggest that vitamin D ameliorates NAFLD and metabolic abnormalities by activating hepatic VDR, leading to its interaction with HNF4?. Our findings highlight a potential value of using vitamin D for preventing and managing NAFLD by targeting VDR.
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