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Time-restricted feeding suppresses excess sucrose-induced plasma and liver lipid accumulation in rats.

ABSTRACT: The etiology of metabolic syndrome involves several complicated factors. One of the main factors contributing to metabolic syndrome has been proposed to be excessive intake of sucrose, which disturbs hepatic lipid metabolism, resulting in fatty liver. However, the mechanism by which sucrose induces fatty liver remains to be elucidated. Considering feeding behavior important for metabolism, we investigated whether time-restricted feeding of high sucrose diet (HSD), only in the active phase (the dark phase of the daily light/dark cycle), would ameliorate adverse effects of sucrose on lipid homeostasis in rats. Male Wistar rats, fed either an ad libitum (ad lib.) or time-restricted control starch diet (CD) or HSD were investigated. Rats fed ad lib. (CD and HSD) completed approximately 20% of food intake in the daytime. Time-restricted feeding did not significantly suppress total food intake of rats. However, time-restricted feeding of HSD significantly suppressed the increased plasma triglyceride levels. Moreover, time-restricted feeding also ameliorated HSD-induced liver lipid accumulation, whereas circadian oscillations of liver clock gene or transcriptional factor gene expression for lipid metabolism were not altered significantly. These results demonstrated that restricting sucrose intake only during the active phase in rats ameliorates the abnormal lipid metabolism caused by excess sucrose intake.

SUBMITTER: Sun S

PROVIDER: S-EPMC6093648 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Time-restricted feeding suppresses excess sucrose-induced plasma and liver lipid accumulation in rats.

Sun Shumin S Hanzawa Fumiaki F Umeki Miki M Ikeda Saiko S Mochizuki Satoshi S Oda Hiroaki H

PloS one 20180815 8

The etiology of metabolic syndrome involves several complicated factors. One of the main factors contributing to metabolic syndrome has been proposed to be excessive intake of sucrose, which disturbs hepatic lipid metabolism, resulting in fatty liver. However, the mechanism by which sucrose induces fatty liver remains to be elucidated. Considering feeding behavior important for metabolism, we investigated whether time-restricted feeding of high sucrose diet (HSD), only in the active phase (the d ...[more]

PMID: 30110343

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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.

Project description:Background/aims:Liver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model. Methods:A novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment. Results:PKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding. Conclusions:Reduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.

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Time-restricted feeding suppresses excess sucrose-induced plasma and liver lipid accumulation in rats.

Publications

Time-restricted feeding suppresses excess sucrose-induced plasma and liver lipid accumulation in rats.

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