title: SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells.
abstract: Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM). The results showed that high glucose induced SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) ameliorated high glucose-induced de-novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells, as demonstrated by a reduction in both secreted apoB and MTP expression, and decreased triglyceride levels and the expression of lipogenic genes such as SREBP1c, FAS and ACC. Overexpression of the SHIP2-DN decreased high glucose-induced apoB containing lipoproteins secretion via reduction in ROS generation, JNK phosphorylation and Akt activation. Furthermore, using the specific inhibitor and activator, it was found that the AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de-novo lipogenesis. Taken together, these findings suggest that SHIP2 is an important regulator of hepatic lipogenesis and lipoprotein secretion in insulin resistance state.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R Iran.
authors.forename: Sattar
authors.initials: S
authors.lastname: Gorgani-Firuzjaee
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R Iran. Electronic address: rmeshkani@tums.ac.ir.
authors.forename: Reza
authors.initials: R
authors.lastname: Meshkani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D015153:Blotting, Western; D015243:Cholesterol, VLDL / Q000096:biosynthesis*; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050155:Lipogenesis / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015243:Cholesterol, VLDL; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D005947:Glucose
keywords: De-novo lipogenesis; HepG2; Hyperglycemia; Insulin resistance; Liver; SH2 domain containing inositol 5-phosphatase (SHIP2); VLDL