title: SH2 domain-containing inositol 5-phosphatase (SHIP2) regulates de-novo lipogenesis and secretion of apoB100 containing lipoproteins in HepG2 cells.
abstract: Hepatic de-novo lipogenesis and production of triglyceride rich VLDL are regulated via the phosphoinositide 3-kinase cascade, however, the role of a negative regulator of this pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we investigated the molecular link between SHIP2 expression and metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells. The results showed that overexpression of the wild type SHIP2 gene (SHIP2-WT) led to a higher total lipid content (28%) compared to control, whereas overexpression of the dominant negative SHIP2 gene (SHIP2-DN) reduced total lipid content in oleate treated cells by 40%. Overexpression of SHIP2-WT also led to a significant increase in both secretion of apoB100 containing lipoproteins and de-novo lipogenesis, as demonstrated by an enhancement in secreted apoB100 and MTP expression, increased intra and extracellular triglyceride levels and enhanced expression of lipogenic genes such as SREBP1c, FAS and ACC. On the other hand, overexpression of the SHIP2-DN gene prevented oleate-induced de-novo lipogenesis and secretion of apoB100 containing lipoproteins in HepG2 cells. Collectively, these findings suggest that SHIP2 expression level is a key determinant of hepatic lipogenesis and lipoprotein secretion, and its inhibition could be considered as a potential target for treatment of dyslipidemia.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
authors.forename: Sattar
authors.initials: S
authors.lastname: Gorgani-Firuzjaee
authors.affiliation: Department of Biochemistry, Institute Pasteur of Iran, Tehran, Islamic Republic of Iran.
authors.forename: Shohreh
authors.initials: S
authors.lastname: Khatami
authors.affiliation: Division of Clinical Biochemistry, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. Electronic address: rmeshkani@tums.ac.ir.
authors.forename: Reza
authors.initials: R
authors.lastname: Meshkani
mesh_terms: D053299:Apolipoprotein B-100 / Q000378:metabolism*; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D050171:Dyslipidemias / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019301:Oleic Acid / Q000494:pharmacology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D007328:Insulin; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D019301:Oleic Acid; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D019735:Carbon-Carbon Ligases; C018757:acyl-CoA carboxylase
keywords: De-novo lipogenesis; HepG2; Insulin resistance; Liver; SH2 domain-containing inositol 5-phosphatase (SHIP2); VLDL