Deficiency of Augmenter of Liver Regeneration is Critical Predisposing Factor for Nonalcoholic Steatohepatitis and Fibrosis

Abstract

Background/AimsThe global incidence of obesity and associated nonalcoholic fatty liver disease (NAFLD) is rising alarmingly. Although majority of subjects develop simple hepatic steatosis, some progress to aggressive inflammatory steatohepatitis (NASH) and then fibrosis/cirrhosis. The cause and diagnostic biomarkers are not defined and there is no treatment. There are no animal models of NASH and NASH‐cirrhosis. Augmenter of liver regeneration protein (ALR) regulates lipid homeostasis and mitochondrial function, suggesting that it may be critical in pathogenesis of NAFLD. We investigated NAFLD in high fat/high carbohydrate (HF/HC)‐fed hepatocyte‐specific ALR‐knockout (ALR‐H‐KO) and ALR‐heterozygous (ALR‐H‐HET) mice, and its relevance to human NASH.MethodsMice were fed chow or HF/HC diet for 16 weeks, and parameters NAFLD/NASH and underlying mechanisms were determined. Hepatic and serum ALR in human NASH‐induced cirrhosis, and in serum of NASH subjects was also measured.ResultsALR‐H‐HET mice develop normally, whereas ALR‐H‐KO mice develop steatohepatitis. Compared to WT mice, HF/HC‐fed ALR‐H‐HET mice gained much more weight and steatosis, and had greater increase in hepatic triglycerides and cholesterol, and differentially altered expression of SREBP1c, CPT1a, ACACA and FAS. HF/HC‐fed ALR‐H‐HET but not WT mice developed fibrosis. In contrast, HF/HC‐fed ALR‐H‐KO mice did not gain weight and had less steatosis but developed cirrhosis. All HF/HC‐fed mice had insulin resistance. Hepatic frequency of TNFα‐, IL6‐ and IL17‐producing cells was greater in ALR‐H‐KO than ALR‐H‐HET and lowest in WT mice. HF/HC did not increase their number in ALR‐H‐KO mice, and increase in ALR‐H‐HET mice was greater than WT mice. Conversely, CD4+CD25+FoxP3+CD4+ regulatory T cell (Treg) frequency was lower in ALR‐H‐HET than WT mice and further reduced in ALR‐H‐KO mice; HF/HC‐feeding reduced Treg in WT but not ALR‐H‐HET or ALR‐H‐KO mice. White adipose tissue (WAT) of HF/HC‐fed ALR‐H‐HET and ALR‐H‐KO mice had strong inflammation indicating bidirectional interactions with the liver, and was consistent with altered hepatic and WAT expression of FGF21, fetuin A and ANGPTL3, which influence de novo lipogenesis and inflammation. Finally, hepatic and serum ALR levels were strongly reduced in patients with NAFLD‐cirrhosis. Serum ALR was also significantly lower in patients with NASH.ConclusionHepatic ALR deficiency is critical predisposing factor for aggressive progression of NAFLD, and serum ALR can be a reliable biomarker of such predisposition. Hepatocyte‐specific ALR‐deficient mouse provides a valuable model to study mechanisms of human NAFLD.Support or Funding InformationW81XWH‐14‐PRMRP‐IIRA and VA Merit Review Award 1IO1BX001174 to CRG; NIH R01DK100314 to RK; NIH P30 DK078392 to the Digestive Diseases Health Center at Cincinnati Children’s Hospital Medical Center