Study of the anti-lipogenic activity of lipids in the liver

Abstract

As demonstrated in the research plan, our omega-3 lipid metabolites are likely to modulate liver function by reducing hepatic lipogenesis and glucose production.Our data also suggest a role for Scd1 in mediating the lipids effects. Scd1 appears to be a major regulator of liver lipogenesis, and its increased activity leads to increased monounsaturated fatty-acids (MUFAs) levels and consequent increased TAG synthesis and hepatic steatosis. This enzyme is responsible for a introduction of a double bond between carbons 9 and 10 on carbons chains of saturated fatty acid, such as stearate (18:0) and palmitate (16:0), for the production of MUFAs. Increased activity of this enzyme increases MUFA levels and consequently leads to increased triacylglyceride synthesis (TAG) in the liver, which is closely linked to nonalcoholic steatohepatitis (NASH). Mouse models of obesity (e.g. leptin-deficient ob/ob mice and high-fat fed DIO mice) have extremely high levels of Scd1 in liver, correlating with hepatic steatosis.In our preliminary studies we found that the omega-3 metabolites, such as 12-HEPE (12-hydroxyecosapentaenoic acid) found in the serum of mice exposed to cold, are capable of reducing Scd1 expression in the liver of DIO mice, perfectly mimicking the cold effects on the liver. Moreover, we found an orphan omega-3 lipid called 14-HDHA, which is biosynthesized by brown fat under cold through the increased 12-Lipoxygease activity and released into the circulation in these conditions. 14-HDHA is a product of the oxidation of docosahexaenoic acid (DHA) at the carbon 14 by the 12-LOX oxidative activity.The 14-HDHA precursor, DHA, is known to exert anti-lipogenic effects in the liver and it has been used as an adjuvant for the treatment of NAFLD in children. Other fatty acids, also produced by 12-Lox, such as Maresine-2 (13R, 14S-dihydroxydocosahexaenoic acid) may be other candidates linked to improvement of hepatic function on exposure to cold.Due to the high doses necessary for its therapeutic activity, it is likely that DHA requires to be metabolized into its active lipid metabolites to exert the anti-lipogenic effects. Our hypothesis is that brown fat converts DHA into 14-HDHA, which is capable of suppressing liver lipogenesis and glucose production by targeting Scd1 and by improving insulin signaling in these cells.Our hypothesis is that TAM is capable of producing 14-HDHA and Maresine-2 from DHA. These products are possibly able to inhibit de novo lipogenesis and hepatic glucose production by inhibiting Scd1 and increasing insulin sensitivity in hepatocytes. In previous experiments, we observed that the exposure of mice to the cold not only suppressed the new hepatic lipogenesis, but also increased levels of 14-HDHA and Maresine-2 in the blood. These findings reinforced the hypothesis that these lipids may be acting to suppress lipogenesis on the liver hepatic. (AU)