Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Abstract

ObjectiveTo examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.DesignTo study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).ResultsHepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.ConclusionsOur study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.

The effect of metabolic surgery on type 1 diabetes: meta-analysis

“…An interesting study showed that transferring microbiota from an obese subject to a lean subject resulted in weight gain (30). The hepatocytes orchestrate the regulatory mechanisms of bile acids, microbiota and metabolome to affect glucose and lipid metabolism (31). Future research may prove the existence of a link between microbiota and beta-cell function.…”

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

“…Receptor activator of NF-κB, a prototypical activator of NF-κB, regulates hepatic insulin sensitivity 184. Deletion of hepatic MyD88 results in liver inflammation and hepatic insulin resistance also affecting the gut microbiota composition and metabolome 185. Therefore, several studies using hepatocyte-specific targeting of genes have now strongly supported the notion that hepatocytes are major metabolic ‘players’ in the development of metabolic inflammation in and beyond the liver.…”

Gut microbiome and liver diseases

“…They found that in absence of MyD88 specifically in the hepatocyte, mice were predisposed to glucose intolerance, inflammation, liver fat accumulation and hepatic insulin resistance, and this was independent of body weight and adiposity 50. In addition, this deletion profoundly affected the gut microbiota composition, therefore, showing that host genetics also contribute to shape the microbiota and in turn host metabolism.…”