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-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. Conclusion 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.

Role of the tumor suppressor IQGAP2 in metabolic homeostasis: possible link between diabetes and cancer

“…The participation of IQGAP2 in several pathways of mammalian cellular signaling, namely Wnt signaling, (GSK3β) and cAMP-PKA signaling (AKAPs) suggests the possibility that IQGAP2 might play a role in cellular energy homeostasis. This notion was supported by the observations [17] that IQGAP2 deficient murine models on a SV129J background displayed enhanced insulin sensitivity and were protected against high fat diet induced hepatic steatosis. Ca2+/calmodulin signaling plays a well-known and crucial role in modulating insulin release by the pancreatic β-cells [18–20].…”

Transcript Profiling Identifies Iqgap2−/− Mouse as a Model for Advanced Human Hepatocellular Carcinoma

“…This pathway is also involved in regulating lipid metabolism. The latter is especially relevant for the Iqgap2 −/− model, since these mice also display a metabolic phenotype linked to a defect in hepatic lipogenesis and fatty acid uptake [21].…”

IQGAPs choreograph cellular signaling from the membrane to the nucleus

“…Interestingly, IQGAP2 knockout mice develop hepatocellular carcinoma, but IQGAP1 and IQGAP2 double knockout mice have normal survival [89], suggesting opposing functions for IQGAP1 and IQGAP2. IQGAP2 also participates in metabolism, as IQGAP2 null mice have impaired uptake of long-chain fatty acids and enhanced insulin sensitivity [96]. The mechanisms that mediate the opposing effects of IQGAP1 and IQGAP2 are unknown.…”