title: Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction.
abstract: Sphingolipids have emerged as important bioactive lipid species involved in the pathogenesis of type 2 diabetes and cardiovascular disease. However, little is known of the regulatory role of sphingolipids in dyslipidemia of insulin-resistant states. We employed hamster models of dyslipidemia and insulin resistance to investigate the role of sphingolipids in hepatic VLDL overproduction, induction of insulin resistance, and inflammation. Hamsters were fed either a control chow diet, a high fructose diet, or a diet high in fat, fructose and cholesterol (FFC diet). They were then treated for 2 weeks with vehicle or 0.3 mg/kg myriocin, a potent inhibitor of de novo sphingolipid synthesis. Both fructose and FFC feeding induced significant increases in hepatic sphinganine, which was normalized to chow-fed levels with myriocin (P < 0.05); myriocin also lowered hepatic ceramide content (P < 0.05). Plasma TG and cholesterol as well as VLDL-TG and -apoB100 were similarly reduced with myriocin treatment in all hamsters, regardless of diet. Myriocin treatment also led to improved insulin sensitivity and reduced hepatic SREBP-1c mRNA, though it did not appear to ameliorate the activation of hepatic inflammatory pathways. Importantly, direct treatment of primary hamster hepatocytes ex vivo with C2 ceramide or sphingosine led to an increased secretion of newly synthesized apoB100. Taken together, these data suggest that a) hepatic VLDL-apoB100 overproduction may be stimulated by ceramides and sphingosine and b) inhibition of sphingolipid synthesis can reduce circulating VLDL in hamsters and improve circulating lipids--an effect that is possibly due to improved insulin signaling and reduced lipogenesis but is independent of changes in inflammation.
authors: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Mark J
authors: MJ
authors: Dekker
authors: Chris
authors: C
authors: Baker
authors: Mark
authors: M
authors: Naples
authors: Josh
authors: J
authors: Samsoondar
authors: Rianna
authors: R
authors: Zhang
authors: Wei
authors: W
authors: Qiu
authors: Jennifer
authors: J
authors: Sacco
authors: Khosrow
authors: K
authors: Adeli
mesh_terms: D000821:Animal Feed; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D006224:Cricetinae; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005632:Fructose / Q000493:pharmacokinetics; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D006505:Hepatitis / Q000188:drug therapy / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013107:Sphingolipids / Q000096:biosynthesis* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D004041:Dietary Fats; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D008079:Lipoproteins, VLDL; C064769:N-acetylsphingosine; D013107:Sphingolipids; D005632:Fructose; D013110:Sphingosine; C005682:safingol; C001996:thermozymocidin