RESUMEN
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.
Asunto(s)
Apolipoproteína B-100/metabolismo , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Ácidos Grasos Monoinsaturados/farmacología , Lipoproteínas VLDL/metabolismo , Esfingolípidos/biosíntesis , Alimentación Animal , Animales , Cricetinae , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Fructosa/farmacocinética , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Hepatitis/tratamiento farmacológico , Hepatitis/metabolismo , Inmunosupresores/farmacología , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Mesocricetus , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismoRESUMEN
Current evidence implicates autophagy in the regulation of lipid stores within the two main organs involved in maintaining lipid homeostasis, the liver and adipose tissue. Critical to this role in hepatocytes is the breakdown of cytoplasmic lipid droplets, a process referred to as lipophagy. Conversely, autophagy is required for adipocyte differentiation and the concurrent accumulation of lipid droplets. Autophagy also affects lipid metabolism through contributions to lipoprotein assembly. A number of reports have now implicated autophagy in the degradation of apolipoprotein B, the main structural protein of very-low-density-lipoprotein. Aberrant autophagy may also be involved in conditions of deregulated lipid homeostasis in metabolic disorders such as the metabolic syndrome. First, insulin signalling and autophagy activity appear to diverge in a mechanism of reciprocal regulation, suggesting a role for autophagy in insulin resistance. Secondly, upregulation of autophagy may lead to conversion of white adipose tissue into brown adipose tissue, thus regulating energy expenditure and obesity. Thirdly, upregulation of autophagy in hepatocytes could increase breakdown of lipid stores controlling triglyceride homeostasis and fatty liver. Taken together, autophagy appears to play a very complex role in lipid homeostasis, affecting lipid stores differently depending on the tissue, as well as contributing to pathways of lipoprotein metabolism.
Asunto(s)
Autofagia/fisiología , Metabolismo de los Lípidos/fisiología , Adipocitos/metabolismo , Animales , Apolipoproteínas B/metabolismo , Autofagia/genética , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos/genética , Lipoproteínas/metabolismoRESUMEN
PURPOSE OF REVIEW: MicroRNAs (miRNAs) regulate gene expression by binding to target mRNAs and control a wide range of biological functions. Recent reports have identified specific miRNAs as major regulators of fatty acid and cholesterol homeostasis. This review examines the biological function of various miRNAs and the emerging evidence linking specific miRNAs to critical pathways in lipid metabolism. RECENT FINDINGS: Disruption of lipid balance can lead to metabolic disturbances and thus tight regulation is required to maintain lipid homeostasis. Recent studies have shown key roles for miR-33 and miR-122 in regulation of lipid metabolism, and further evidence implicates miR-370 in regulation of miR-122. In addition, miRNAs involved in adipogenesis (miR-378/378* and miR-27) as well as newly discovered miRNAs such as miR-613, miR-302a, and miR-168 have now been implicated in regulation of lipid metabolism. SUMMARY: Growing evidence support key roles for miRNAs in regulating both cholesterol and fatty acid metabolism, leading to considerable interest in miRNAs as potential drug targets to modulate lipid and lipoprotein metabolism. MiRNA-based therapeutics hold considerable promise in the fight to curtail the growing epidemic of obesity and type 2 diabetes and the associated risk of atherosclerosis.