Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy

Lin, Yu‐Cheng; Chang, Pi-Feng; Lin, Hsueh-Fang; Liu, Kevin; Chang, Mei–Hwei; Ni, Yen‐Hsuan

doi:10.1016/j.jhep.2016.06.029

Cited by 73 publications

(64 citation statements)

References 33 publications

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“…It is plausible that Irgm1 could play a direct role in lipid homeostasis, because it is a dynamin-like GTPase that associates with specific intracellular membrane compartments, including the Golgi, where it may alter membrane trafficking (11,12,21,25,52,78,87). Additionally, IRGM proteins have been reported to play roles in lipid droplet maintenance (27,78,88). The novel role for Irgm1, and perhaps other IRG proteins, in modulating fatty acid accumulation and metabolism establishes a new direction for research to unravel the roles of IRG proteins in the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-␥ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In the studies reported here, we found that uninfected Irgm1-deficient mice displayed high levels of serum cytokines typifying profound autoinflammation. Similar increases in cytokine production were also seen in cultured, IFN-␥-primed macrophages that lacked Irgm1. A series of metabolic studies indicated that the enhanced cytokine production was associated with marked metabolic changes in the Irgm1-deficient macrophages, including increased glycolysis and an accumulation of long chain acylcarnitines. Cells were exposed to the glycolytic inhibitor, 2-deoxyglucose, or fatty acid synthase inhibitors to perturb the metabolic alterations, which resulted in dampening of the excessive cytokine production. These results suggest that Irgm1 deficiency drives metabolic dysfunction in macrophages in a manner that is cell-autonomous and independent of infectious triggers. This may be a significant contributor to excessive inflammation seen in Irgm1-deficient mice in different contexts.

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Section: Discussionmentioning

confidence: 99%

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Schmidt

Fee

Henry

et al. 2017

Journal of Biological Chemistry

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“…This protein is perhaps best characterized for its role in the autophagic clearance of bacteria [106]. Interestingly, in addition to a reduction in xenophagy, knockdown or naturally occurring mutations of this protein result in increased hepatic lipid accumulation [107,108]. Clearly, a number of targets connected broadly to the autophagic pathway have intricate links to the turnover of hepatic LDs.…”

Section: Lipophagy In Disease Statesmentioning

confidence: 99%

Breaking fat: The regulation and mechanisms of lipophagy

Schulze

Sathyanarayan

Mashek

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

189

115

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Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). While the field of lipophagy research is relatively young, an expansion of research in this area over the past several years has greatly advanced our understanding of lipophagy. Since its original characterization in fasted liver, the contribution of lipophagy is now recognized in various organisms, cell types, metabolic states and disease models. Moreover, recent studies provide exciting new insights into the underlying mechanisms of lipophagy induction as well as the consequences of lipophagy on cell metabolism and signaling. This review summarizes recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as our understanding of lipophagy continues to grow and evolve.

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“…Virally encoded structural (core) and nonstructural (NS5A) proteins are embedded on the LD surface, allowing for efficient HCV virion production . HCV also appears to target another host cell lipophagy‐related factor, the immunity‐related GTPase family M protein, in order to promote efficient replication . Reduced immunity‐related GTPase family M expression is capable of not only interfering with autophagic progression but also negatively impacting viral replication, suggesting an important role for this lipophagy‐related gene in the pathogenesis of hepatitis viruses.…”

Section: Other Roles For Hepatic Lipophagymentioning

confidence: 99%

Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver

Schulze

Drižytė

Casey

et al. 2017

Hepatology Communications

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The liver is a central fat‐storage organ, making it especially susceptible to steatosis as well as subsequent inflammation and cirrhosis. The mechanisms by which the liver mobilizes stored lipid for energy production, however, remain incompletely defined. The catabolic process of autophagy, a well‐known process of bulk cytoplasmic recycling and cellular self‐regeneration, is a central regulator of lipid metabolism in the liver. In the past decade, numerous studies have examined a selective form of autophagy that specifically targets a unique neutral lipid storage organelle, the lipid droplet, to better understand the function for this process in hepatocellular fatty acid metabolism. In the liver (and other oxidative tissues), this specialized pathway, lipophagy, likely plays as important a role in lipid turnover as conventional lipase‐driven lipolysis. In this review, we highlight several recent studies that have contributed to our understanding about the regulation and effects of hepatic lipophagy. (Hepatology Communications 2017;1:359–369)

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Variants in the autophagy-related gene IRGM confer susceptibility to non-alcoholic fatty liver disease by modulating lipophagy

Cited by 73 publications

References 33 publications

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

Breaking fat: The regulation and mechanisms of lipophagy

Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver

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