PMID- 21520168
OWN - NLM
STAT- MEDLINE
DCOM- 20110719
LR  - 20211020
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 53
IP  - 5
DP  - 2011 May
TI  - Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid 
      accumulation and liver injury in alcohol-induced steatosis in mice.
PG  - 1526-37
LID - 10.1002/hep.24256 [doi]
AB  - Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated 
      hypoxia-inducible factor 1-alpha, (HIF-1alpha) may regulate liporegulatory genes, but the 
      relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1alpha in 
      alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in 
      steatosis, increased liver triglyceride levels, and increased serum alanine 
      aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. 
      There was increased hepatic HIF-1alpha messenger RNA (mRNA), protein, and DNA-binding 
      activity in alcohol-fed mice compared with controls. Mice engineered with 
      hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1alpha mRNA, 
      protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased 
      hepatomegaly and hepatic triglyceride compared with WT mice. In contrast, 
      hepatocyte-specific deletion of HIF-1alpha [HIF-1alpha(Hep(-/-) )], protected mice from 
      alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, 
      hepatomegaly, and lipid accumulation. HIF-1alpha(Hep(-/-) ), WT, and HIF1dPA mice had 
      equally suppressed levels of peroxisome proliferator-activated receptor alpha mRNA 
      after chronic ethanol, whereas the HIF target, adipocyte differentiation-related 
      protein, was up-regulated in WT mice but not HIF-1alpha(Hep(-/-) ) 
      ethanol-fed/LPS-challenged mice. The chemokine monocyte chemoattractant protein-1 
      (MCP-1) was cooperatively induced by alcohol feeding and LPS in WT but not 
      HIF-1alpha(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 
      treatment induced lipid accumulation and increased HIF-1alpha protein expression as 
      well as DNA-binding activity. Small interfering RNA inhibition of HIF-1alpha 
      prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for 
      HIF-1alpha in hepatocyte lipid accumulation. CONCLUSION: Alcohol feeding results in 
      lipid accumulation in hepatocytes involving HIF-1alpha activation. The 
      alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via 
      HIF-1alpha activation, suggesting a mechanistic link between inflammation and hepatic 
      steatosis in alcoholic liver disease.
CI  - Copyright (c) 2011 American Association for the Study of Liver Diseases.
FAU - Nath, Bharath
AU  - Nath B
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA, USA.
FAU - Levin, Ivan
AU  - Levin I
FAU - Csak, Timea
AU  - Csak T
FAU - Petrasek, Jan
AU  - Petrasek J
FAU - Mueller, Christian
AU  - Mueller C
FAU - Kodys, Karen
AU  - Kodys K
FAU - Catalano, Donna
AU  - Catalano D
FAU - Mandrekar, Pranoti
AU  - Mandrekar P
FAU - Szabo, Gyongyi
AU  - Szabo G
LA  - eng
GR  - R21 AA017545/AA/NIAAA NIH HHS/United States
GR  - R01 AA017986/AA/NIAAA NIH HHS/United States
GR  - P30 DK032520/DK/NIDDK NIH HHS/United States
GR  - DK32520/DK/NIDDK NIH HHS/United States
GR  - F30 AA017030/AA/NIAAA NIH HHS/United States
GR  - R21 AA017544-02/AA/NIAAA NIH HHS/United States
GR  - F30 AA017030-04/AA/NIAAA NIH HHS/United States
GR  - R21 AA017544/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
MH  - Animals
MH  - Fatty Liver, Alcoholic/*metabolism
MH  - Hepatocytes/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*physiology
MH  - *Lipid Metabolism
MH  - Mice
PMC - PMC3104403
MID - NIHMS274328
EDAT- 2011/04/27 06:00
MHDA- 2011/07/20 06:00
PMCR- 2012/05/01
CRDT- 2011/04/27 06:00
PHST- 2011/04/27 06:00 [entrez]
PHST- 2011/04/27 06:00 [pubmed]
PHST- 2011/07/20 06:00 [medline]
PHST- 2012/05/01 00:00 [pmc-release]
AID - 10.1002/hep.24256 [doi]
PST - ppublish
SO  - Hepatology. 2011 May;53(5):1526-37. doi: 10.1002/hep.24256.