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dc.contributor.authorNath, Bharath D.
dc.contributor.authorLevin, Ivan
dc.contributor.authorCsak, Timea
dc.contributor.authorPetrasek, Jan
dc.contributor.authorMueller, Christian
dc.contributor.authorKodys, Karen
dc.contributor.authorCatalano, Donna
dc.contributor.authorMandrekar, Pranoti
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:36.000
dc.date.accessioned2022-08-23T16:01:12Z
dc.date.available2022-08-23T16:01:12Z
dc.date.issued2011-05-01
dc.date.submitted2012-10-10
dc.identifier.citation<p>Hepatology. 2011 May;53(5):1526-37. doi: 10.1002/hep.24256. <a href="http://dx.doi.org/10.1002/hep.24256" target="_blank">Link to article on publisher's site</a></p>
dc.identifier.issn0270-9139 (Linking)
dc.identifier.doi10.1002/hep.24256
dc.identifier.pmid21520168
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31066
dc.description.abstractChronic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=21520168&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104403/pdf/nihms274328.pdf
dc.subjectAnimals
dc.subjectFatty Liver, Alcoholic
dc.subjectHepatocytes
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.subject*Lipid Metabolism
dc.subjectMice
dc.subjectDigestive System Diseases
dc.subjectGastroenterology
dc.titleHepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice
dc.typeJournal Article
dc.source.journaltitleHepatology (Baltimore, Md.)
dc.source.volume53
dc.source.issue5
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gastroenterology_pp/123
dc.identifier.contextkey3383621
html.description.abstract<p>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.</p> <p>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.</p>
dc.identifier.submissionpathgastroenterology_pp/123
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentGene Therapy Center
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology
dc.source.pages1526-37


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