Augmenter of liver regeneration: Mitochondrial function and steatohepatitis

Augmenter of liver regeneration (ALR), a ubiquitous fundamental life protein, is expressed more abun-dantly in the liver than other organs. Expression of ALR is highest in hepatocytes, which also constitu-tively secrete it. ALR gene transcription is regulated by NRF2, FOXA2, SP1, HNF4a, EGR-1 and AP1/AP4. ALR's FAD-linked sulfhydryl oxidase activity is essential for protein folding in the mitochondrial inter -membrane space. ALR's functions also include cytochrome c reductase and protein Fe/S maturation ac-tivities. ALR depletion from hepatocytes leads to increased oxidative stress, impaired ATP synthesis and apoptosis/necrosis. Loss of ALR's functions due to homozygous mutation causes severe mitochondrial defects and congenital progressive multiorgan failure, suggesting that individuals with one functional ALR allele might be susceptible to disorders involving compromised mitochondrial function. Genetic ablation of ALR from hepatocytes induces structural and functional mitochondrial abnormalities, dys-regulation of lipid homeostasis and development of steatohepatitis. High-fat diet-fed ALR-deficient mice develop non-alcoholic steatohepatitis (NASH) and fibrosis, while hepatic and serum levels of ALR are lower than normal in human NASH and NASH-cirrhosis. Thus, ALR deficiency may be a critical predis-posing factor in the pathogenesis and progression of NASH.(c) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Automated summary

Augmenter of liver regeneration (ALR) is a protein that is expressed more abundantly in the liver than other organs. It plays important roles in protein folding, cytochrome c reductase activity, and protein Fe/S maturation. ALR deficiency in hepatocytes leads to oxidative stress, impaired ATP synthesis, and increased apoptosis/necrosis. Individuals with one functional ALR allele may be susceptible to disorders involving compromised mitochondrial function.