| Abstract: | Augmenter of liver regeneration (ALR), a ubiquitous fundamental life protein, is expressed more abundantly in the liver than other organs. Hepatocytes, the major cells expressing ALR in several subcellular compartments including mitochondria, also secrete it constitutively. ALR gene transcription is regulated by NRF2, FOXA2, SP1, HNF4α, EGR-1 and AP1/AP4. ALR's FAD-linked sulfhydryl oxidase activity is essential for protein folding in the mitochondrial intermembrane space. ALR's functions also include cytochrome c reductase and protein Fe/S maturation activities. 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, dysregulation of lipid homeostasis and development of steatohepatitis. Whereas high-fat diet-fed ALR-deficient mice develop nonalcoholic steatohepatitis (NASH) and fibrosis, hepatic and serum levels of ALR are lower than normal in human NASH and NASH-cirrhosis. Thus ALR deficiency may be a critical predisposing cause for the pathogenesis and progression of NASH. |
