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Gut. 2017 Apr;66(4):620-632. doi: 10.1136/gutjnl-2015-310904. Epub 2016 May 5.

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

Author information

1
WELBIO- Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
2
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
3
Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain.
4
de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
5
Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg, Sweden.
6
Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
7
Laboratory of Hepatology, University of Leuven (KUL), Belgium.
8
Department of Gastroenterology and Hepatology, Division of Liver and Biliopancreatic Disorders, KUL, Leuven, Belgium.
9
Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

OBJECTIVE:

To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.

DESIGN:

To 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).

RESULTS:

Hepatocyte-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.

CONCLUSIONS:

Our 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.

KEYWORDS:

BILE ACID METABOLISM; DIABETES MELLITUS; GLUCOSE METABOLISM; INTESTINAL BACTERIA; LIPID METABOLISM

PMID:
27196572
PMCID:
PMC5529962
DOI:
10.1136/gutjnl-2015-310904
[Indexed for MEDLINE]
Free PMC Article

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