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Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.

ABSTRACT: Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic disease, and carried out quantitative proteomic analysis of liver mitochondria. As previously reported, proteins involved in fatty acid oxidation, branched chain amino acid degradation, tricarboxylic acid cycle, and oxidative phosphorylation were uniformly up-regulated in the liver of HFD fed mice compared with that of normal diet. Further, our studies revealed that retinol metabolism is distinctly down-regulated and the mitochondrial structural proteins-components of mitochondrial inter-membrane space bridging (MIB) complex (Mitofilin, Sam50, and ChChd3), and Tim proteins-essential for protein import, are significantly up-regulated in HFD fed mice. Structural and functional studies on HFD and normal diet liver mitochondria revealed remodeling of HFD mitochondria to a more condensed form with increased respiratory capacity and higher ATP levels compared with normal diet mitochondria. Thus, it is likely that the structural remodeling is essential to accommodate the increased protein content in presence of HFD: the mechanism could be through the MIB complex promoting contact site and crista junction formation and in turn facilitating the lipid and protein uptake.

SUBMITTER: Guo Y

PROVIDER: S-EPMC3861721 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.

Guo Yurong Y Darshi Manjula M Ma Yuliang Y Perkins Guy A GA Shen Zhouxin Z Haushalter Kristofer J KJ Saito Rintaro R Chen Ai A Lee Yun Sok YS Patel Hemal H HH Briggs Steven P SP Ellisman Mark H MH Olefsky Jerrold M JM Taylor Susan S SS

Molecular & cellular proteomics : MCP 20130912 12

Insulin resistance plays a major role in the development of type 2 diabetes and obesity and affects a number of biological processes such as mitochondrial biogenesis. Though mitochondrial dysfunction has been linked to the development of insulin resistance and pathogenesis of type 2 diabetes, the precise mechanism linking the two is not well understood. We used high fat diet (HFD)-induced obesity dependent diabetes mouse models to gain insight into the potential pathways altered with metabolic d ...[more]

PMID: 24030101

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Project description:Nonalcoholic fatty liver disease (NAFLD) is becoming a primary cause of liver damage in Western society. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD and may lead to liver cancer. Our previous long-term murine studies have shown the beneficial role of Aquamin, a red marine algae-derived (calcium, magnesium, additional trace elements-rich) supplement, in reducing liver injury and decreasing liver tumor incidence. The main objective of the study was to determine how manifestations and effects of NASH can be mitigated using Aquamin. We hypothesized that mice on a high-fat Western diet (HFWD) with minerals would exhibit less liver injury than mice on a HFWD without minerals. Methods: Two cohorts of MS-NASH mice (8-week-old) were placed on a HFWD with and without minerals for 16 weeks. An additional cohort of MS-NASH mice on the same HFWD was treated with obeticholic acid (OCA). C57BL/6 mice on a regular chow were included as a control. During the in-life phase of the study, weight changes were assessed weekly. At termination, livers were histologically assessed for steatosis and fibrosis by using hematoxylin and eosin, and picrosirius red staining. Liver tissue samples were also subjected to tandem mass tag (TMT) mass-spectroscopic proteomics for protein expression profile in individual mice. Results: Mice on HFWD gained more weight than mice on control diet, but there was no overall change in weight for mice on HFWD, irrespective of interventions. On histological assessment, there was no difference in steatosis between the two high-fat groups, but mice on Aquamin showed reduced picrosirius red staining or collagen deposition as compared to placebo on HFWD mice. Regarding proteomic profile, there was a clear distinction among control and HFWD groups. Placebo (on HFWD) mice were used for comparison. Aquamin intervention altered 91 proteins while OCA altered 84 proteins in liver samples with a 2-fold change. Of these, 57 proteins were common between Aquamin and OCA. Most of the proteins were upregulated. Aquamin upregulated 39 unique pathways (with a p-value <0.05) as assessed by the Reactome database. Some of the pathways significantly impacted by Aquamin were formation of cornified envelope; keratinization; gap junction assembly; type I hemidesmosome assembly; apoptosis-related; plasma lipoprotein assembly, remodeling and clearance; and hedgehog “off” state pathways. Proteins downregulated by OCA are mainly involved in the synthesis of bile acids and bile salts. Conclusion: The addition of dietary minerals may play a protective role in interfering with downstream advancement from steatosis to NASH. Our studies provide mechanistic insight into how mineral supplementation may contribute to the reduction in liver injury and tumor formation (one of the most devastating consequences) of fatty liver disease in the context of HFWD-induced steatosis.

Dataset Information

Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.

Publications

Quantitative proteomic and functional analysis of liver mitochondria from high fat diet (HFD) diabetic mice.

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