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Regulation of Hepatic Lipid Accumulation and Distribution by Agouti-Related Protein in Male Mice.

ABSTRACT: Proper regulation of energy metabolism requires neurons in the central nervous system to respond dynamically to signals that reflect the body's energy reserve, and one such signal is leptin. Agouti-related protein (AgRP) is a hypothalamic neuropeptide that is markedly upregulated in leptin deficiency, a condition that is associated with severe obesity, diabetes, and hepatic steatosis. Because deleting AgRP in mice does not alter energy balance, we sought to determine whether AgRP plays an indispensable role in regulating energy and hepatic lipid metabolism in the sensitized background of leptin deficiency. We generated male mice that are deficient for both leptin and AgRP [double-knockout (DKO)]. DKO mice and ob/ob littermates had similar body weights, food intake, energy expenditure, and plasma insulin levels, although DKO mice surprisingly developed heightened hyperglycemia with advancing age. Overall hepatic lipid content was reduced in young prediabetic DKO mice, but not in the older diabetic counterparts. Intriguingly, however, both young and older DKO mice had an altered zonal distribution of hepatic lipids with reduced periportal lipid deposition. Moreover, leptin stimulated, whereas AgRP inhibited, hepatic sympathetic activity. Ablating sympathetic nerves to the liver, which primarily innervate the portal regions, produced periportal lipid accumulation in wild-type mice. Collectively, our results highlight AgRP as a regulator of hepatic sympathetic activity and metabolic zonation.

SUBMITTER: Maier MT

PROVIDER: S-EPMC6692877 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Regulation of Hepatic Lipid Accumulation and Distribution by Agouti-Related Protein in Male Mice.

Maier Matthew T MT Vilhelmsson Anna A Louie Sharon M SM Vagena Eirini E Nomura Daniel K DK Koliwad Suneil K SK Xu Allison W AW

Endocrinology 20180601 6

Proper regulation of energy metabolism requires neurons in the central nervous system to respond dynamically to signals that reflect the body's energy reserve, and one such signal is leptin. Agouti-related protein (AgRP) is a hypothalamic neuropeptide that is markedly upregulated in leptin deficiency, a condition that is associated with severe obesity, diabetes, and hepatic steatosis. Because deleting AgRP in mice does not alter energy balance, we sought to determine whether AgRP plays an indisp ...[more]

PMID: 29750244

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Project description:Background & aimsCurrently, only a few genetic variants explain the heritability of fatty liver disease. Quantitative trait loci (QTL) analysis of mouse strains has identified the susceptibility locus Ltg/NZO (liver triglycerides from New Zealand obese [NZO] alleles) on chromosome 18 as associating with increased hepatic triglycerides. Herein, we aimed to identify genomic variants responsible for this association.MethodsRecombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and characterized for liver fat. Bioinformatic analysis, mRNA profiles and electrophoretic mobility shift assays were performed to identify genes responsible for the Ltg/NZO phenotype. Candidate genes were manipulated in vivo by injecting specific microRNAs into C57BL/6 mice. Pulldown coupled with mass spectrometry-based proteomics and immunoprecipitation were performed to identify interaction partners of IFGGA2.ResultsThrough positional cloning, we identified 2 immunity-related GTPases (Ifgga2, Ifgga4) that prevent hepatic lipid storage. Expression of both murine genes and the human orthologue IRGM was significantly lower in fatty livers. Accordingly, liver-specific suppression of either Ifgga2 or Ifgga4 led to a 3-4-fold greater increase in hepatic fat content. In the liver of low-fat diet-fed mice, IFGGA2 localized to endosomes/lysosomes, while on a high-fat diet it associated with lipid droplets. Pulldown experiments and proteomics identified the lipase ATGL as a binding partner of IFGGA2 which was confirmed by co-immunoprecipitation. Both proteins partially co-localized with the autophagic marker LC3B. Ifgga2 suppression in hepatocytes reduced the amount of LC3B-II, whereas overexpression of Ifgga2 increased the association of LC3B with lipid droplets and decreased triglyceride storage.ConclusionIFGGA2 interacts with ATGL and protects against hepatic steatosis, most likely by enhancing the binding of LC3B to lipid droplets.Lay summaryThe genetic basis of non-alcoholic fatty liver disease remains incompletely defined. Herein, we identified members of the immunity-related GTPase family in mice and humans that act as regulators of hepatic fat accumulation, with links to autophagy. Overexpression of the gene Ifgga2 was shown to reduce hepatic lipid storage and could be a therapeutic target for the treatment of fatty liver disease.

Dataset Information

Regulation of Hepatic Lipid Accumulation and Distribution by Agouti-Related Protein in Male Mice.

Publications

Regulation of Hepatic Lipid Accumulation and Distribution by Agouti-Related Protein in Male Mice.

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