eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH.

Autor:	Sheldon RD; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Meers GM; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Morris EM; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas., Linden MA; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Cunningham RP; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Ibdah JA; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri., Thyfault JP; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.; Kansas City Veterans Affairs Medical Center, Kansas City, Missouri., Laughlin MH; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri., Rector RS; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.; Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri.; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2019 Oct 01; Vol. 317 (4), pp. E605-E616. Date of Electronic Publication: 2019 Jul 30.
DOI:	10.1152/ajpendo.00096.2019
Abstrakt:	Dysregulated mitochondrial quality control leads to mitochondrial functional impairments that are central to the development and progression of hepatic steatosis to nonalcoholic 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 purified primary hepatocytes and in vitro siRNA-induced knockdown of eNOS. Hepatic mitochondria from eNOS knockout mice revealed decreased markers of mitochondrial biogenesis (PPARγ coactivator-1α, mitochondrial transcription factor A) and autophagy/mitophagy [BCL-2-interacting protein-3 (BNIP3), 1A/1B light chain 3B (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 wild-type mice. Finally, we demonstrate that eNOS is required in primary hepatocytes to induce activation of the stress-responsive transcription factor nuclear factor erythroid 2-related factor 2 ( NRF2 ). Thus, our data demonstrate that eNOS is an important regulator of hepatic mitochondrial content and function and NASH susceptibility.
Databáze:	MEDLINE
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