Hepatic MyD88 regulates liver Inflammation by altering the synthesis of oxysterols.

This study aims to investigate the function of hepatic MyD88, a central adaptor of innate immunity, on metabolism. Although its role in inflammation is well known, we have recently discovered that MyD88 can also mediate energy, lipid and glucose metabolism.More precisely, we have reported that mice harboring hepatocyte-specific deletion of MyD88 (Myd88ΔHep) were predisposed to glucose intolerance, liver fat accumulation and inflammation. However, the molecular events explaining the onset of hepatic disorders and inflammation remain to be elucidated. To investigate the molecular mechanism, Myd88ΔHepand WT mice were challenged by two complementary approaches affecting liver lipid metabolism and immunity. The first one consisted of a short-term exposure to HFD whereas the second was an acute LPS injection. We discovered thatupon 3 days of HFD, Myd88ΔHepmice displayed an increase in liver weight and liver lipids as compared to WT mice. Moreover, we found that bile acid and oxysterol metabolism were deeply affected by the absence of hepatic MyD88. Our data suggest that the negative feedback loop suppressing bile acid synthesis was impaired (i.e., ERK activity was decreased) in Myd88ΔHepmice. Finally, the predisposed inflammation sensitivity displayed by Myd88ΔHepmice may be caused by the accumulation of 25-OHC, an oxysterol linked to inflammatory response and metabolic disorders. This study highlights the importance of MyD88 on both liver fat accumulation and cholesterol-deri...
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Tags: Am J Physiol Endocrinol Metab Source Type: research