Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and tissue damage in nonalcoholic fatty liver disease

Abstract

To overcome the rising burdens of nonalcoholic fatty liver disease, mechanistic linkages in mitochondrial dysfunction, inflammation and hepatic injury are critical. As ataxia telangiectasia mutated (ATM) gene oversees DNA integrity and mitochondrial homeostasis, we analyzed mRNAs and total proteins or phosphoproteins related to ATM gene by arrays in subjects with healthy liver, fatty liver or nonalcoholic steatohepatitis. Functional genomics approaches were used to query DNA damage or cell growth events. The effects of fatty acid-induced toxicity in mitochondrial health, DNA integrity and cell proliferation were validated in HuH-7 cells, including by inhibiting ATM kinase activity or knckdown of its mRNA. In fatty livers, DNA damage and ATM pathway activation was observed. During induced steatosis in HuH-7 cells, lowering of ATM activity produced mitochondrial dysregulation, DNA damage and cell growth inhibition. In livers undergoing steatohepatitis, ATM was depleted with increased hepatic DNA damage and growth-arrest due to cell cycle checkpoint activations. Moreover, molecular signatures of oncogenesis were associated with upstream mechanistic networks directing cell metabolism, inflammation or growth that were either activated (in fatty liver) or inactivated (in steatohepatitis). To compensate for hepatic growth arrest, preoncogenic oval cell populations expressing connexin-43 and/or albumin emerged. These oval cells avoided DNA damage and proliferated actively. We concluded that ATM is a major contributor to the onset and progression of nonalcoholic fatty liver disease. Therefore, specific markers for ATM pathway dysregulation will allow prospective segregation of cohorts for disease susceptibility and progression from steatosis to steatohepatitis. This will offer superior design and evaluation parameters for clinical trials. Restoration of ATM activity with targeted therapies should be appropriate for nonalcoholic fatty liver disease.

Keywords: DNA damage response; Gene expression; Inflammation; Liver regeneration; Steatohepatitis.