Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis

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• 作者：Milica Bozic¹ ; Carla Guzmá ; n² ; Marta Benet² ; Sonia Sá ; nchez-Campos³ ; ⁵ ; Carmelo Garcí ; a-Monzó ; n⁴ ; ⁵ ; Eloi Gari⁶ ; Sonia Gatius⁷ ; José ; Manuel Valdivielso¹ ; ^&dagger ; ; ^{valdivielso@medicina.udl.es" class="auth_mail" title="E-mail the corresponding author} ; Ramiro Jover² ; ⁵ ; ⁸ ; ^&dagger ; ; ^{ramiro.jover@uv.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：apoE ; apolipoprotein E ; BA ; bile acids ; CAR ; constitutive androstane receptor ; CD36 ; cluster of differentiation 36 or fatty acid translocase (FAT) ; CEBPα ; transcription factor CCAAT/enhancer binding protein α ; DGAT2 ; diacylglycerol O-acyltransferase 2 ; eWAT ; epididymal white adipose tissue ; FA ; fatty acid ; FGF21 ; fibroblast growth factor 21 ; FXR ; farnesoid X receptor ; GAPDH ; glyceraldehyde 3-phosphate dehydrogenase ; HDL ; high density lipoprotein ; HFD ; high fat diet ; IR ; insulin resistance ; LC-MS
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：65
• 期：4
• 页码：748-757
• 全文大小：1681 K

文摘

The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated.

Methods

The expression of liver VDR was investigated in apolipoprotein E knockout (apoE^−/−) mice on a high fat diet, in wild-type mice on methionine and choline deficient diet and in NAFLD patients with hepatosteatosis and non-alcoholic steatohepatitis. The relevance of VDR was assessed in apoE^−/− mice by deletion of VDR or paricalcitol treatment and in human HepG2 cells by VDR transfection or silencing. The role of VDR in fibrosis was also determined in VDR knockout mice (VDR^−/−) treated with thioacetamide.

Results

Expression of liver VDR was markedly induced in two mouse models of NAFLD, as well as in patients with hepatosteatosis, but decreased in non-alcoholic steatohepatitis. VDR deletion in high fat diet-fed apoE^−/− mice protected against fatty liver, dyslipidemia and insulin resistance, and caused a decrease in taurine-conjugated bile acids, but did not influence fibrosis by thioacetamide. apoE^−/−VDR^−/− mouse livers showed decreased gene expression of CD36, DGAT2, C/EBPα and FGF21, and increased expression of PNPLA2, LIPIN1 and PGC1α. Treatment of apoE^−/− mice on high fat diet with paricalcitol had modest opposite effects on steatosis and gene expression. Finally, this set of genes showed concordant responses when VDR was overexpressed or silenced in HepG2 cells.

Conclusions

Induced hepatocyte VDR in NAFLD regulates key hepatic lipid metabolism genes and promotes high fat diet-associated liver steatosis. Therapeutic inhibition of liver VDR may reverse steatosis in early NAFLD.

Lay summary

The amount of vitamin D receptor is induced early in the livers of mice and humans when they develop non-alcoholic fatty liver disease. If the gene for the vitamin D receptor is deleted, hepatic lipid metabolism changes and mice do not accumulate fat in the liver. We conclude that the vitamin D receptor can contribute to the fatty liver disease promoted by a high fat diet.