The progression of NAFLD is influenced by suppression of two immune-related GTPases

K Schwerbel; A Kamitz; M Jähnert; P Gottmann; F Schumacher; B Kleuser; T Haltenhof; F Heyd; M Roden; A Chadt; H Al-Hasani; W Jonas; H Vogel; A Schürmann

doi:10.1055/s-0038-1641761

Diabetologie und Stoffwechsel, Table of Contents

Diabetologie und Stoffwechsel 2018; 13(S 01): S2
DOI: 10.1055/s-0038-1641761

Freie Vorträge

Freie Vorträge Adipositas-Fettgewebe-Leber

Georg Thieme Verlag KG Stuttgart · New York

The progression of NAFLD is influenced by suppression of two immune-related GTPases

K Schwerbel

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

,

A Kamitz

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

,

M Jähnert

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

,

P Gottmann

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

³German Diabetes Center (DDZ), München-Neuherberg, Germany

,

F Schumacher

⁴University of Potsdam, Institute of Nutritional Science, Potsdam, Germany

,

B Kleuser

⁴University of Potsdam, Institute of Nutritional Science, Potsdam, Germany

,

T Haltenhof

⁵Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany

,

F Heyd

⁵Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany

,

M Roden

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

⁶German Diabetes Center (DDZ), Institute for Clinical Diabetology, Düsseldorf, Germany

⁷Heinrich-Heine University, Department of Endocrinology and Diabetology, Düsseldorf, Germany

,

A Chadt

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

⁸German Diabetes Center (DDZ), Institute for Clinical Biochemistry and Pathobiochemistry, Düsseldorf, Germany

,

H Al-Hasani

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

⁸German Diabetes Center (DDZ), Institute for Clinical Biochemistry and Pathobiochemistry, Düsseldorf, Germany

,

W Jonas

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

,

H Vogel

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

,

A Schürmann

¹German Institute of Human Nutrition (DIfE), Department of Experimental Diabetology, Potsdam-Rehbruecke, Germany

²German Center for Diabetes Research (DZD), München-Neuherberg, Germany

› Author Affiliations

Abstract

Full Text

Background/Aim:

The cause of non-alcoholic fatty liver disease (NAFLD) is multifactorial including genetic and environmental factors. In a backcross population of New Zealand obese (NZO) and C57BL/6J (B6) mice, a major quantitative trait locus (QTL), Ltg/NZO on chromosome 18, for increased liver triglycerides was identified. The aim of the study is to characterize the role and function of two causal gene variants of Ltg/NZO in vivo.

Methods:

Recombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and metabolically characterized concerning their hepatic insulin sensitivity and lipid profile. Bioinformatics analysis and Electrophoretic Mobility Shift Assay (EMSA) were performed to elucidate the genetic cause for the differential expression pattern.

Results:

NZO-allele carriers (Ltg/NZO ^N/N) showed 2-fold higher liver triglyceride concentration than B6-allele carriers (Ltg/NZO ^N/B). Furthermore, Ltg/NZO ^N/N revealed impaired hepatic insulin sensitivity in line with higher diacylglycerol levels. Haplotype mapping and expression studies identified two immune-related GTPases as most likely candidates of Ltg/NZO which were 5 – 20-fold lower expressed in livers of Ltg/NZO ^N/N compared to Ltg/NZO ^N/Bmice. An upstream active enhancer element harboring a FOXO1-binding motif was identified carrying a single nucleotide deletion in Ltg/NZO ^N/Nalleles. This alteration could be explained by an impaired FOXO1 binding. Moreover, the human orthologue IRGM is significantly lower expressed in the liver of NAFLD patients compared to that of lean subjects.

Conclusion:

A sufficient expression of IRGM and its orthologous prevent the hepatic accumulation of triglycerides in humans and mice.