Abstract
AbstractClinical studies demonstrated that nonalcoholic steatohepatitis is associated with liver-related outcomes in chronic hepatitis B. Furthermore, primary biliary fibrosis and biliary atresia occurred in patients with HBV infection. Interestingly, hepatitis B virus surface protein (HBs) transgenic mice spontaneously develop hepatic steatosis. Our aim is to investigate the effect of Abcb4 knockout-induced cholestasis on liver steatosis in HBs transgenic mice. Hybrids of HBs transgenic and Abcb4−/− mice were bred on the BALB/c genetic background. Lipid synthesis, storage, and catabolism as well as proteins and genes that control lipid metabolism were analyzed using HPTLC, qPCR, western blot, electrophoretic mobility shift assay (EMSA), lipid staining, and immunohistochemistry. Hepatic neutral lipid depots were increased in HBs transgenic mice and remarkably reduced in Abcb4−/− and HBs/Abcb4−/− mice. Similarly, HPTLC-based quantification analyses of total hepatic lipid extracts revealed a significant reduction in the amount of triacylglycerols (TAG), while the amount of free fatty acids (FFA) was increased in Abcb4−/− and HBs/Abcb4−/− in comparison to wild-type and HBs mice. PLIN2, a lipid droplet-associated protein, was less expressed in Abcb4−/− and HBs/Abcb4−/−. The expression of genes-encoding proteins involved in TAG synthesis and de novo lipogenesis (Agpat1, Gpat1, Mgat1, Dgat1, Dgat2, Fasn, Hmgcs1, Acc1, Srebp1-c, and Pparγ) was suppressed, and AMPK and CREB were activated in Abcb4−/− and HBs/Abcb4−/− compared to wild-type and HBs mice. Simulating cholestatic conditions in cell culture resulted in AMPK and CREB activation while FASN and PLIN2 were reduced. A concurrent inhibition of AMPK signaling revealed normal expression level of FASN and PLIN2, suggesting that activation of AMPK–CREB signaling regulates hepatic lipid metabolism, i.e. synthesis and storage, under cholestatic condition. In conclusions, in vivo and mechanistic in vitro data suggest that cholestasis reduces hepatic lipid storage via AMPK and CREB signaling. The results of the current study could be the basis for novel therapeutic strategies as NASH is a crucial factor that can aggravate chronic liver diseases.The authors demonstrate that cholestasis impairs hepatic lipid storage via AMP-activated protein kinase (AMPK) and CREB signaling in hepatitis B virus surface protein transgenic mice. The pharmacological modulation of AMPK and CREB signaling might be a promising therapeutic concept for the treatment of fatty liver diseases.
Highlights
IntroductionPhosphatidylcholines are essential for the formation of bile acid-containing micelles, a crucial process in protecting cholangiocyte membranes from being exposed to high concentrations of free cell-toxic bile acids (BA) [2]
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.The injury of bile ducts is a hallmark of chronic cholestatic liver disorders of multifactorial origin leading to hepatic accumulation of bile acids (BA) and subsequent liver tissue damage [1, 2]
We investigated the effects of Abcb4−/−-induced cholestasis in two distinct models, Abcb4-deficient mice (Abcb4−/−) and hepatitis B virus surface protein (HBs) overexpressing mice as well as chimera of both, knockout and transgene, on BALB/c genetic background (HBs, HBs/Abcb4−/−)
Summary
Phosphatidylcholines are essential for the formation of bile acid-containing micelles, a crucial process in protecting cholangiocyte membranes from being exposed to high concentrations of free cell-toxic BA [2]. Similar to human cholestatic liver diseases, Abcb knockout mice develop liver fibrosis, multiple derangements of lipid metabolism, including alterations in cholesterol and phospholipid metabolism [3, 4]. Chronic viral hepatitis (CVH) implies liver damage causing liver fibrosis and subsequent hepatocellular carcinoma formation [5]. It has been shown recently in a large combined tertiary center cohort that patients with concomitant nonalcoholic steatohepatitis (NASH) and chronic hepatitis B infection had poorer clinical outcomes [6]. Apart from steatosis, further histopathological changes have been reported in the same transgenic model including inflammation, regenerative hyperplasia, endoplasmatic reticulum stress, and associated unfolded protein response [9,10,11]
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