Reduced hepatic cholesterol secretion and augmented intestinal cholesterol absorption exacerbate the development of nonalcoholic fatty liver disease and the progression from liver steatosis to nonalcoholic steatohepatitis in Abcg8 knockout mice

Abstract

BackgroundHigh dietary cholesterol (Ch) is a critical risk factor for the development of nonalcoholic fatty liver disease (NAFLD). The ATP‐binding cassette sterol transporter G5/G8 (Abcg5/g8) plays a key role in determining hepatic Ch secretion and intestinal sterol absorption. Although Ch is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double‐ or single‐knockout (KO) mice, hepatic Ch output is dramatically reduced. In addition, intestinal Ch absorption is augmented by ~30% in sitosterolemic patients and mice with deficiency in intestinal Abcg5 or Abcg8. However, it is largely unknown whether reduced hepatic Ch output and enhanced intestinal Ch absorption aggravate NAFLD and NASH. Our aim is to explore whether targeted deletion of the Abcg8 gene leads to a rapid development of liver steatosis and its progression to nonalcoholic steatohepatitis (NASH) in mice fed a high‐fat diet plus even a low amount of Ch compared to wild‐type (WT) mice.MethodsThe effect of Abcg8 on NAFLD and NASH was investigated by pathology methods in male Abcg8 KO vs WT mice fed a chow diet (containing trace Ch <0.02%) on day 0, and a high‐fat diet with 60% kcal from fat plus 0.1% Ch for 12 wk. Hepatic cholesterol secretion was determined by a cannulation of the common bile duct for collecting the first hour of hepatic bile. Hepatic Ch output, as well as liver lipid concentrations were measured by biochemical methods. Intestinal Ch absorption efficiency was analyzed by Ch balance methods.ResultsOn chow (day 0), biliary Ch output is significantly reduced in Abcg8 KO mice (3.6±0.4 μmol/h/kg) compared to that in WT mice (11.5±2.8 μmol/h/kg). Moreover, intestinal Ch absorption efficiency is significantly increased in Abcg8 KO mice (63±10%) compared to that in WT mice (45±5%). At 12 wk of feeding the high‐fat diet plus 0.1% Ch, biliary Ch output is still lower in Abcg8 KO mice (4.1±0.5 μmol/h/kg) than in WT mice (15.1±0.7 μmol/h/kg). In contrast, liver Ch esters, Ch, and triglyceride (TG) concentrations are significantly higher in Abcg8 KO mice (Ch esters=156.7±52.1 mg/g, Ch=1.8±0.6 mg/g, and TG=269±78 mg/g) compared to those in WT mice (Ch esters=20.3±4.6 mg/g, Ch=0.7±0.2 mg/g, and TG=123±35 mg/g). Furthermore, Abcg8 KO mice develop not only severe liver steatosis, but also NASH with substantial inflammatory infiltrate and perisinusoidal fibrosis, whereas only moderate liver steatosis with little inflammatory infiltrate and no fibrosis is detected in WT mice.ConclusionsReduced hepatic Ch secretion and increased intestinal Ch absorption caused by deletion of the Abcg8 gene in the liver and intestine leads to the accumulation of large amounts of Ch in the liver, thereby enhancing susceptibility to the development of NAFLD and the progression from liver steatosis to NASH in high‐fat‐diet‐fed Abcg8 KO mice in challenge to a low‐Ch diet. Our findings suggest that humans with underexpression or mutation of either the ABCG5 or ABCG8 gene may be predisposed to rapidly develop NAFLD and NASH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.