PMID- 31361543
OWN - NLM
STAT- MEDLINE
DCOM- 20200323
LR  - 20201001
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 317
IP  - 4
DP  - 2019 Oct 1
TI  - eNOS deletion impairs mitochondrial quality control and exacerbates Western 
      diet-induced NASH.
PG  - E605-E616
LID - 10.1152/ajpendo.00096.2019 [doi]
AB  - 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 (PPARgamma coactivator-1alpha, 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.
FAU - Sheldon, Ryan D
AU  - Sheldon RD
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Nutrition and Exercise Physiology, University of Missouri, 
      Columbia, Missouri.
FAU - Meers, Grace M
AU  - Meers GM
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Nutrition and Exercise Physiology, University of Missouri, 
      Columbia, Missouri.
FAU - Morris, E Matthew
AU  - Morris EM
AD  - Department of Molecular and Integrative Physiology, University of Kansas Medical 
      Center, Kansas City, Kansas.
FAU - Linden, Melissa A
AU  - Linden MA
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Nutrition and Exercise Physiology, University of Missouri, 
      Columbia, Missouri.
FAU - Cunningham, Rory P
AU  - Cunningham RP
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Nutrition and Exercise Physiology, University of Missouri, 
      Columbia, Missouri.
FAU - Ibdah, Jamal A
AU  - Ibdah JA
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Medicine, Division of Gastroenterology and Hepatology, University 
      of Missouri, Columbia, Missouri.
FAU - Thyfault, John P
AU  - Thyfault JP
AD  - Department of Molecular and Integrative Physiology, University of Kansas Medical 
      Center, Kansas City, Kansas.
AD  - Kansas City Veterans Affairs Medical Center, Kansas City, Missouri.
FAU - Laughlin, M Harold
AU  - Laughlin MH
AD  - Department of Biomedical Sciences, University of Missouri, Columbia, Missouri.
FAU - Rector, R Scott
AU  - Rector RS
AD  - Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, 
      Missouri.
AD  - Department of Medicine, Division of Gastroenterology and Hepatology, University 
      of Missouri, Columbia, Missouri.
AD  - Department of Nutrition and Exercise Physiology, University of Missouri, 
      Columbia, Missouri.
LA  - eng
GR  - I01 BX003271/BX/BLRD VA/United States
GR  - K01 DK112967/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190730
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (BNip3 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Autophagy/genetics
MH  - Diet, Western/*adverse effects
MH  - Gene Knockdown Techniques
MH  - Hepatocytes/pathology
MH  - Male
MH  - Membrane Proteins/biosynthesis/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitochondria, Liver/*metabolism
MH  - Mitochondrial Proteins/biosynthesis/genetics
MH  - Mitophagy
MH  - NF-E2-Related Factor 2/biosynthesis/genetics
MH  - Nitric Oxide Synthase Type III/*genetics
MH  - Non-alcoholic Fatty Liver Disease/*genetics/*metabolism
MH  - Primary Cell Culture
MH  - RNA, Small Interfering/pharmacology
PMC - PMC6842915
OTO - NOTNLM
OT  - NAFLD
OT  - endothelial nitric oxide synthase
OT  - mitophagy
OT  - steatohepatitis
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2019/07/31 06:00
MHDA- 2020/03/24 06:00
PMCR- 2020/10/01
CRDT- 2019/07/31 06:00
PHST- 2019/07/31 06:00 [pubmed]
PHST- 2020/03/24 06:00 [medline]
PHST- 2019/07/31 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - E-00096-2019 [pii]
AID - 10.1152/ajpendo.00096.2019 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2019 Oct 1;317(4):E605-E616. doi: 
      10.1152/ajpendo.00096.2019. Epub 2019 Jul 30.