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Multi-omics approach reveals dysregulation of protein phos-phorylation correlated with lipid metabolism in mouse fatty liver

ABSTRACT: Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used multi-omics approach by conducting comparative proteomic, phoshopro-teomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites (with localization probability > 0.75), of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Uma Aryal

PROVIDER: MSV000088835 | MassIVE | Mon Feb 14 12:58:00 GMT 2022

REPOSITORIES: MassIVE

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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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Multi-omics approach reveals dysregulation of protein phos-phorylation correlated with lipid metabolism in mouse fatty liver

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