PMID- 34003729
OWN - NLM
STAT- MEDLINE
DCOM- 20211011
LR  - 20220401
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 65
IP  - 4
DP  - 2021 Oct
TI  - Hepatocyte HIF-1 and Intermittent Hypoxia Independently Impact Liver Fibrosis in 
      Murine Nonalcoholic Fatty Liver Disease.
PG  - 390-402
LID - 10.1165/rcmb.2020-0492OC [doi]
AB  - Obstructive sleep apnea is associated with insulin resistance, lipid 
      dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver 
      disease (NAFLD). We have previously shown that hepatocyte HIF-1 
      (hypoxia-inducible factor-1) mediates the development of liver fibrosis in a 
      mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling 
      obstructive sleep apnea would worsen hepatic steatosis and fibrosis in murine 
      NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a (Hif1a(-/-)hep) 
      and wild-type (Hif1a(F/F)) controls were fed a high trans-fat diet to induce 
      NAFLD with steatohepatitis. Half from each group were exposed to IH, and the 
      other half were exposed to intermittent air. A glucose tolerance test was 
      performed just prior to the end of the experiment. Mitochondrial efficiency was 
      assessed in fresh liver tissue at the time of death. The hepatic malondialdehyde 
      concentration and proinflammatory cytokine levels were assessed, and genes of 
      collagen and fatty acid metabolism were examined. Hif1a(-/-)hep mice gained less 
      weight than wild-type Hif1a mice (-2.3 g, P = 0.029). There was also a 
      genotype-independent effect of IH on body weight, with less weight gain in mice 
      exposed to IH (P = 0.003). Fasting glucose, homeostatic model assessment for 
      insulin resistance, and glucose tolerance test results were all improved in 
      Hif1a(-/-)hep mice. Liver collagen was increased in mice exposed to IH 
      (P = 0.033) and was reduced in Hif1a(-/-)hep mice (P < 0.001), without any 
      significant exposure/genotype interaction being demonstrated. Liver TNF-alpha and 
      IL-1beta were significantly increased in mice exposed to IH and were decreased in 
      Hif1a(-/-)hep mice. We conclude that HIF-1 signaling worsens the metabolic 
      profile and hastens NAFLD progression and that IH may worsen liver fibrosis. 
      These effects are plausibly mediated by hepatic inflammatory stress.
FAU - Mesarwi, Omar A
AU  - Mesarwi OA
AUID- ORCID: 0000-0003-3102-6468
AD  - Division of Pulmonary, Critical Care, and Sleep Medicine, University of 
      California San Diego School of Medicine, La Jolla, California.
FAU - Moya, Esteban A
AU  - Moya EA
AD  - Division of Pulmonary, Critical Care, and Sleep Medicine, University of 
      California San Diego School of Medicine, La Jolla, California.
FAU - Zhen, Xin
AU  - Zhen X
AD  - University of California San Diego School of Medicine, La Jolla, California.
FAU - Gautane, Mary
AU  - Gautane M
AD  - University of California San Diego School of Medicine, La Jolla, California.
FAU - Zhao, Huyai
AU  - Zhao H
AD  - University of California San Diego School of Medicine, La Jolla, California.
FAU - Wegbrans Giro, Paula
AU  - Wegbrans Giro P
AD  - Department of Bioengineering, Imperial College London, London, United Kingdom.
FAU - Alshebli, Mouza
AU  - Alshebli M
AD  - Abu Dhabi Health Services Company, Abu Dhabi, United Arab Emirates; and.
FAU - McCarley, Kendall E
AU  - McCarley KE
AD  - Department of Educational Psychology, University of Houston, Houston, Texas.
FAU - Breen, Ellen C
AU  - Breen EC
AD  - Division of Pulmonary, Critical Care, and Sleep Medicine, University of 
      California San Diego School of Medicine, La Jolla, California.
FAU - Malhotra, Atul
AU  - Malhotra A
AD  - Division of Pulmonary, Critical Care, and Sleep Medicine, University of 
      California San Diego School of Medicine, La Jolla, California.
LA  - eng
GR  - K08 HL143140/HL/NHLBI NIH HHS/United States
GR  - P30 NS047101/NS/NINDS NIH HHS/United States
GR  - T32 HL134632/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
CIN - Am J Respir Cell Mol Biol. 2021 Oct;65(4):337-338. PMID: 34101539
MH  - Animals
MH  - Diet, High-Fat/adverse effects
MH  - Disease Models, Animal
MH  - Hepatocytes/*metabolism/pathology
MH  - Hypoxia/*complications/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*deficiency/metabolism
MH  - Insulin Resistance/physiology
MH  - Lipid Metabolism/immunology
MH  - Liver/metabolism
MH  - Liver Cirrhosis/complications/*metabolism/pathology
MH  - Mice
MH  - Non-alcoholic Fatty Liver Disease/*metabolism
PMC - PMC8525205
OTO - NOTNLM
OT  - HIF-1
OT  - hepatic fibrosis
OT  - hyperglycemia
OT  - lipid metabolism
OT  - obstructive sleep apnea
EDAT- 2021/05/19 06:00
MHDA- 2021/10/12 06:00
PMCR- 2022/03/30
CRDT- 2021/05/18 17:12
PHST- 2021/05/19 06:00 [pubmed]
PHST- 2021/10/12 06:00 [medline]
PHST- 2021/05/18 17:12 [entrez]
PHST- 2022/03/30 00:00 [pmc-release]
AID - 10.1165/rcmb.2020-0492OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2021 Oct;65(4):390-402. doi: 10.1165/rcmb.2020-0492OC.