Papel de las prostaglandinas producidas por la ciclooxigenasa-2 en la resistencia a la insulina asociada a la enfermedad hepática grasa no alcohólica

Abstract

Cyclooxygenase (COX) is the enzyme that catalyzes the limiting step in prostanoid biosynthesis pathway, including prostaglandins (PGs). There are two isoforms of COX; COX-1 is constitutively expressed in many tissues, and COX-2, which is induced by variety stimuli such as growth and pro-inflammatory factors, and cell stress. Adult hepatocytes fail to induce COX-2 expression, regardless of the pro-inflammatory factors used, however, after partial hepatectomy for liver regeneration, in viral hepatitis, hepatoma cell lines and hepatocellular carcinoma (HCC), the hepatocytes are able to express it. The insulin resistance (IR) is involved in the pathophysiology of obesity-related diseases such as type 2 diabetes mellitus and non-alcoholic fatty liver disease (NAFLD). In addition, the IR is associated with a state of mild chronic inflammation that contributes significantly to its development. Previous studies have implicated COX-2 in the pathophysiology of obesity and IR with contradictory results. Given this background, we studied the involvement of COX-2 in a model of liver damage, IR and altered metabolism homeostasis induced by a high fat diet (HFD) in transgenic mice for human COX-2 (Tg). Moreover, we analyzed the effect of COX-2 in modulating the expression of microRNAs (miRNAs) and their possible role in liver pathology related to IR and NAFLD. Our results show that the expression of COX-2 in hepatocytes protects against IR, hepatic steatosis and adiposity induced by HFD in mice, due to increased insulin sensitivity and glucose tolerance induced by AKT and AMPK activation in the liver, a reduction of pro-inflammatory cytokines, and liver and plasma lipids associated with an enhanced mitochondrial oxidation, and increased energy expenditure and induction of thermogenesis. Furthermore, the results suggest a novel mechanism by which the expression of COX-2 in hepatocytes protects against IR in liver cells. PGs derived from COX-2 reduce the levels of miR-23b, miR-146b and miR-183 by stabilizing DDX5 via PI3K / AKT / p300. Moreover, COX-2 inhibits the biogenesis of these miRNAs by modulating the activity of Drosha complex via physical association with DDX5. Consequently, the expression of his target gene IRS1, key in insulin signaling, increases. Besides, an inverse correlation between the expression of COX-2 and miRNAs has been demonstrated in patients with non-alcoholic steatosis.