eNOS Deletion Impairs Mitochondrial Quality Control and Exacerbates Western Diet Induced NASH.

eNOS Deletion Impairs Mitochondrial Quality Control and Exacerbates Western Diet Induced NASH. Am J Physiol Endocrinol Metab. 2019 Jul 30;: Authors: Sheldon RD, Meers GM, Morris EM, Linden MA, Cunningham RP, Ibdah JA, Thyfault JP, Laughlin MH, Rector RS Abstract Dysregulated mitochondrial quality control leads to mitochondrial functional impairments that are central to the development and progression of hepatic steatosis to steatohepatitis (NASH). Here we identify hepatocellular localized endothelial nitric oxide synthase (eNOS) as a novel master regulator of mitochondrial quality control. Mice lacking eNOS were more susceptible to western diet induced hepatic inflammation and fibrosis in conjunction with decreased markers of mitochondrial biogenesis and turnover. The hepatocyte specific influence was verified via Magnetic Activated Cell Sorting (MACS) purified primary hepatocytes and in vitro siRNA induced knock down of eNOS. Hepatic mitochondria from eNOS knockout mice revealed decreased markers of mitochondrial biogenesis (PGC1α, TFAM) and autophagy/mitophagy (BNIP3, LC3), suggesting decreased mitochondrial turnover rate. eNOS knockout in primary hepatocytes exhibited reduced fatty acid oxidation capacity and were unable to mount a normal BNIP3 response to a mitophagic challenge compared with WT mice. Finally, we demonstrate that eNOS is required in primary hepatocytes to induce activation of the stress responsive transcription f...
Source: Am J Physiol Endocri... - Category: Endocrinology Authors: Tags: Am J Physiol Endocrinol Metab Source Type: research