AUTHOR=Hoebinger Constanze , Rajcic Dragana , Silva Beatriz , Hendrikx Tim 

TITLE=Chronic-binge ethanol feeding aggravates systemic dyslipidemia in Ldlr-/- mice, thereby accelerating hepatic fibrosis

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1148827

DOI=10.3389/fendo.2023.1148827

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>Chronic ethanol consumption is known to cause alcohol-associated liver disease, which poses a global health concern as almost a quarter of heavy drinkers develop severe liver damage. Alcohol-induced liver disease ranges from a mild, reversible steatotic liver to alcoholic steatohepatitis and irreversible liver fibrosis and cirrhosis, ultimately requiring liver transplantation. While ethanol consumption is associated with dysregulated lipid metabolism and altered cholesterol homeostasis, the impact of dyslipidemia and pre-existing hypercholesterolemia on the development of alcohol-associated liver disease remains to be elucidated.</p></sec><sec><title>Design</title><p>To address the influence of systemic dyslipidemia on ethanol-induced liver disease, chronic-binge ethanol feeding was applied to female C57BL/6J (wild type) mice and mice deficient for the low-density lipoprotein receptor (<italic>Ldlr<sup>-/-</sup></italic>), which display a human-like lipoprotein profile with elevated cholesterol and triglyceride levels in circulation. Respective control groups were pair-fed an isocaloric diet.</p></sec><sec><title>Results</title><p>Chronic-binge ethanol feeding did not alter systemic lipid levels in wild type mice. While increased systemic cholesterol levels in <italic>Ldlr<sup>-/-</sup></italic> mice were not affected by ethanol feeding, chronic-binge ethanol diet aggravated elevated plasma triglyceride levels in <italic>Ldlr<sup>-/-</sup></italic> mice. Despite higher circulatory triglyceride levels in <italic>Ldlr<sup>-/-</sup></italic> mice, hepatic lipid levels and the development of hepatic steatosis were not different from wild type mice after ethanol diet, while hepatic expression of genes related to lipid metabolism (<italic>Lpl</italic>) and transport (<italic>Cd36</italic>) showed minor changes. Immunohistochemical assessment indicated a lower induction of infiltrating neutrophils in the livers of ethanol-fed <italic>Ldlr<sup>-/-</sup></italic> mice compared to wild type mice. In line, hepatic mRNA levels of the pro-inflammatory genes <italic>Ly6g</italic>, <italic>Cd11b</italic>, <italic>Ccr2</italic>, <italic>Cxcl1</italic> and <italic>F4/80</italic> were reduced, indicating less inflammation in the livers of <italic>Ldlr<sup>-/-</sup></italic> mice which was associated with reduced <italic>Tlr9</italic> induction. While systemic ALT and hepatic MDA levels were not different, <italic>Ldlr</italic>-deficient mice showed accelerated liver fibrosis development after chronic-binge ethanol diet than wild type mice, as indicated by increased levels of Sirius Red staining and higher expression of pro-fibrotic genes <italic>Tgfb</italic>, <italic>Col1a1</italic> and <italic>Col3a1</italic>. <italic>Ldlr<sup>-/-</sup></italic> and wild type mice had similar plasma ethanol levels and did not show differences in the hepatic mRNA levels of <italic>Adh1</italic> and <italic>Cyp2e1</italic>, important for ethanol metabolism.</p></sec><sec><title>Conclusion</title><p>Our results highlight that chronic-binge ethanol feeding enhances systemic dyslipidemia in <italic>Ldlr<sup>-/-</sup></italic> mice which might accelerate the development of hepatic fibrosis, independent of hepatic lipid levels.</p></sec>