Dual-acting glucagon-like peptide-1/glucagon receptor agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly those requiring PH. (Hepatology 2017;65:950-968).

Epidemiological and animal studies suggest an association between dietary fatty acids and an increase risk of developing breast cancer. Obesity, which is characterized by hyperlipidemia and an elevation of circulating free fatty acids (FFAs), is also associated with enhanced cancer risk. In breast cancer cells, the FFA oleic acid (OA) induces migration, proliferation, prolong survival, invasion, an increase in cellular Ca(2+) concentration, MEK1/2, ERK1/2, FAK and Src activation. However, the role of OA on MMP-9 secretion and invasion has not been studied in detail. We demonstrate here that stimulation of MDA-MB-231 breast cancer cells with 200 μM OA induces an increase on MMP-9 secretion through a PKC, Src, and EGFR-dependent pathway, as revealed by gelatin zymography assays. Furthermore, microtubule network mediates MMP-9 secretion induced by OA. In contrast, OA does not induce an increase on MMP-9 secretion in MCF10A cells, whereas it does not induce MMP-9 secretion in MCF12A mammary non-tumorigenic epithelial cells. In addition, OA induces invasion through an EGFR, Gi/Go proteins, MMPs, PKC and Src-dependent pathway, but it is not able to promote invasion in non-invasive MCF-7 breast cancer cells. In summary, our findings demonstrate that OA promotes an increase on MMP-9 secretion and invasion through a PKC, Src, and EGFR-dependent pathway in breast cancer cells.

No abstract

Accumulation evidence links obesity-induced inflammation as an important contributor to the development of insulin resistance, which plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. Cyclooxygenase (COX)-1 and -2 catalyze the first step in prostanoid biosynthesis. Because adult hepatocytes fail to induce COX-2 expression regardless of the proinflammatory stimuli used, we have evaluated whether this lack of expression under mild proinflammatory conditions might constitute a permissive condition for the onset of insulin resistance. Our results show that constitutive expression of human COX-2 (hCOX-2) in hepatocytes protects against adiposity, inflammation, and, hence, insulin resistance induced by a high-fat diet, as demonstrated by decreased hepatic steatosis, adiposity, plasmatic and hepatic triglycerides and free fatty acids, increased adiponectin-to-leptin ratio, and decreased levels of proinflammatory cytokines, together with an enhancement of insulin sensitivity and glucose tolerance. Furthermore, hCOX-2 transgenic mice exhibited increased whole-body energy expenditure due in part by induction of thermogenesis and fatty acid oxidation. The analysis of hepatic insulin signaling revealed an increase in insulin receptor-mediated Akt phosphorylation in hCOX-2 transgenic mice. In conclusion, our results point to COX-2 as a potential therapeutic target against obesity-associated metabolic dysfunction.Insulin resistance (IR) plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. IR is the key primary defect underlying the development of type 2 diabetes and is a central component defining the metabolic syndrome. That IR is associated with a state of chronic low-grade inflammation has been demonstrated, and inflammation is assumed to contribute in a major way to its development (1). Besides the fact that IR is characterized by complex interactions between genetic determinants and nutritional factors, it is recognized that mediators synthesized from immune cells and adipocytes are involved in the regulation of insulin action (2). Insulin acts in target cells by binding to its specific receptor and activating a cascade of intracellular signaling events that are altered in inflammation-associated IR (3).Inflammation induces the expression of a variety of proteins, including prostaglandin-endoperoxide synthase-2, also known as cyclooxygenase (COX)-2, which catalyzes the first step in prostanoid biosynthesis. COX-2 is induced by a variety of stimuli such as growth factors, proinflammatory mediators, hormones, and other cellular