Involvement of exercise-induced macrophage migration inhibitory factor in the prevention of fatty liver disease

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Abstract

Physical inactivity can lead to obesity and fat accumulation in various tissues. Critical complications of obesity include type II diabetes and nonalcoholic fatty liver disease (NAFLD). Exercise has been reported to have ameliorating effects on obesity and NAFLD. However, the underlying mechanism is not fully understood. We showed that liver expression of macrophage migration inhibitory factor (MIF) was increased after 4 weeks of treadmill exercise. Phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in human hepatocyte cell lines was enhanced after MIF treatment. These responses were accompanied by increases in lipid oxidation. Moreover, inhibition of either AMPK or cluster of differentiation 74 resulted in inhibition of MIF-induced lipid oxidation. Furthermore, the administration of MIF to a human hepatocyte cell line and mice liver reduced liver X receptor agonist-induced lipid accumulation. Taken together, these results indicate that MIF is highly expressed in the liver during physical exercise and may prevent hepatic steatosis by activating the AMPK pathway.

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Most cited references 25

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The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.

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MIF Signal Transduction Initiated by Binding to CD74

Lin Leng, Christine Metz, YAN FANG … (2003)

Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal–regulated kinase–1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of ∼9 × 10−9 K d, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal–regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.

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Molecular mediators of hepatic steatosis and liver injury.

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Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.

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Author and article information

Journal

Journal ID (nlm-ta): J Endocrinol

Journal ID (iso-abbrev): J. Endocrinol

Journal ID (publisher-id): JOE

Title: The Journal of Endocrinology

Publisher: BioScientifica (Bristol )

ISSN (Print): 0022-0795

ISSN (Electronic): 1479-6805

Publication date (Print): August 2013

Publication date (Electronic preprint): 3 July 2013

Volume: 218

Issue: 3

Pages: 339-348

Affiliations

[1]BioSignal Network Laboratory School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology Engineering Building 104689-805, UlsanRepublic of Korea

[1 ]Division of Molecular and Life Sciences Pohang University of Science and Technology (POSTECH) Pohang, KyungbukRepublic of Korea

[2 ]Lee Gil Ya Cancer and Diabetes Institute and Gil Medical Center, Korea Mouse Metabolic Phenotyping Center Gachon University Incheon, 406-840Republic of Korea

Author notes

(Correspondence should be addressed to P-G Suh; Email: pgsuh@ 123456unist.ac.kr )

Article

Publisher ID: JOE130135

DOI: 10.1530/JOE-13-0135

PMC ID: 3757527

PubMed ID: 23823021

SO-VID: 634a9f70-9efb-432d-86c7-8c8c37a8f43c

License:

This work is licensed under a Creative Commons Attribution 3.0 Unported License

History

Date revision received : 13 June 2013

Date accepted : 1 July 2013

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