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Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis

ABSTRACT: Genetic predisposition and environmental components contribute to an individuals’ non-alcoholic fatty liver disease (NAFLD) susceptibility. Therefore, we compared phenotypic variations of mouse strains extensively used in biomedical research during induction of high-fat diet (HFD)-mediated NAFLD and assessed transcriptional alterations in livers. In a time-resolved fashion we determined a wide spectrum of physiological parameters in C3HeB/FeJ (C3H), C57BL/6NTac, C57BL/6J, and 129P2/OlaHsd (129) males during a 7, 14, or 21 days HFD challenge and performed gene transcription analyses in steatotic livers. HFD exposure for 21 days progressively increased liver triacylglycerol concentrations (TAG) in 129. Strain-specific liver transcription profiles in this model suggest a transition from benign fatty liver to inflammation-associated NAFLD. No comparable changes were observed in C3H males where after an initial increase, hepatic TAG declined. In all genetic backgrounds hepatosteatosis was paralleled by a concerted repression of genes potentially increasing the liver’s vulnerability to oxidative stress damage thereby contributing to the progression of benign hepatosteatosis to NASH later on. The products of further identified strain-independent gene candidates might represent putative molecular links between the pathogenesis of NAFLD and cancer, insulin resistance, type 2 diabetes, and neurodegenerative disorders. Phenotypic characteristics and strain-dependent and -independent transcriptional changes in liver in different murine genetic backgrounds in this work can be exploited in the search for molecular mechanisms implicated in the development of HFD-mediated NAFLD, the investigation of potential therapeutic targets and in selecting a suitable murine genetic background for studies and mouse mutant engineering.

ORGANISM(S): Mus musculus

PROVIDER: GSE43106 | GEO | 2015/10/06

SECONDARY ACCESSION(S): PRJNA184410

REPOSITORIES: GEO

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Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

Project description:High Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods, and its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the exact molecular mechanisms by which HFCS impacts hepatic metabolism are still unclear, especially in the context of obesity. In contrast, the vast majority of current studies in the field focus either on the detrimental role of fructose on NAFLD or compare the additive impact of fructose versus glucose in this process. Besides, studies elaborating on the role of fructose in NAFLD utilize molecular fructose, rather than HFCS, thus lacking simulation of human NAFLD in a more realistic way. Herein, by engaging combined omic approaches, we sought to characterize the additive impact of HFCS on NAFLD during obesity and recognize candidate pathways and molecules which could mediate the exaggeration of steatosis under these conditions. To achieve this goal, C57BL/6 male mice were fed a normal-fat (ND), a high-fat (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic and lipidomic analyses were conducted and utilized separately or in an integrated mode to identify HFCS-related molecular alterations of the hepatic metabolic landscape. Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed greater aggravation of hepatic steatosis. Importantly, the HFD-HFCS hepatic proteome was characterized by an upregulation of the enzymes implicated in de novo lipogenesis (DNL), while palmitic-acid containing diglycerides were significantly increased in the HFD-HFCS hepatic lipidome, as compared to the HFD group. Integrated omic analysis further suggested that TCA cycle overstimulation, is likely contributing towards the intensification of steatosis in the HFD-HFCS dietary theme. Overall, our results imply that HFCS may significantly contribute to NAFLD aggravation during obesity, with its fructose-rich properties being the main suspect.

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Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis

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