title: Ablation of Iqgap2 protects from diet-induced hepatic steatosis due to impaired fatty acid uptake.
abstract: Long-chain fatty acids (LCFA) serve as structural components for membrane biogenesis and as primary energy sources during mitochondrial β-oxidation reactions. Hepatic LCFA uptake is complex, with characteristics suggestive of a dual-kinetic model manifested by rapid (carrier-assisted/facilitated) and delayed (passive diffusional) phases. Our previous work using mice deficient of the Iqgap2 gene established a highly novel link between IQGAP2, a putative GTPase-activating protein, and hepatocarcinogenesis. Now we report that Iqgap2 deficiency also results in selective loss of the facilitated phase of hepatocyte LCFA uptake with preservation of the diffusional component. This molecular defect was seen in Iqgap2(-/-) hepatocytes of all ages studied (1-, 4-, 8-months). The loss of facilitated LCFA uptake protected against development of hepatic triglyceride accumulation in Iqgap2-deficient mice fed high-fat diet, consistent with a fundamental role in physiological fat partitioning. These phenotypic changes could not be explained by genetic loss of fatty acid processing proteins known to regulate lipid uptake or metabolic processing pathways. Iqgap2-deficient livers also displayed enhanced insulin sensitivity.
  
  
  CONCLUSIONS
  These observations identify a novel property of the putative GTPase-activating protein IQGAP2 in LCFA uptake in vitro and in vivo, and implicate IQGAP2 in an intracellular signaling pathway necessary for functional fatty acid uptake, lipid processing, and, possibly, glucose homeostasis.
authors.affiliation: Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Carmine S
authors.initials: CS
authors.lastname: Chiariello
authors.forename: Joseph F
authors.initials: JF
authors.lastname: LaComb
authors.forename: Wadie F
authors.initials: WF
authors.lastname: Bahou
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology*; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D015430:Weight Gain; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D002614:Chelating Agents; D005230:Fatty Acids, Nonesterified; C484416:Iqgap2 protein, mouse; D047493:PPAR alpha; D014280:Triglycerides; D020703:ras GTPase-Activating Proteins; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D064429:Fatty Acid Synthases