Liver lipidome signature and metabolic pathways in nonalcoholic fatty liver disease induced by a high-sugar diet |
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| Institution: | 1. Laboratório de Bioquímica e Biologia Molecular, Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brasil;2. Laboratório de Fisiologia Molecular e Metabolismo, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, São Paulo, Brasil;3. Laboratório de Lipídeos Modificados, Departamento de Bioquímica, Universidade de São Paulo, São Paulo, Brasil;4. Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brasil;1. Laboratory of Experimental Physiology, Department of Physiological Sciences, Federal University of Maranhão, São Luís, (MA), Brazil;2. Laboratory of Vascular Biology, Heart Institute of the School of Medicine, University of São Paulo, São Paulo, (SP), Brazil;1. USDA-ARS Grand Forks Human Nutrition Research Center Grand Forks, North Dakota, USA;2. Department of Chemistry, University of North Dakota, Grand Forks, North Dakota, USA;3. Department of Pathology, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, USA;1. Laboratory of Modified Lipids, Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil;2. Nutritional Genomics and Inflammation Laboratory, Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil;3. Food Research Center (FoRC), CEPID-FAPESP, Research Innovation and Dissemination Centers São Paulo Research Foundation, São Paulo, Brazil |
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| Abstract: | Dietary sugar is an important determinant of the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the deleterious effects of sugar intake on NAFLD under energy-balanced conditions are still poorly understood. Here, we provide a comprehensive analysis of the liver lipidome and mechanistic insights into the pathogenesis of NAFLD induced by the chronic consumption of high-sugar diet (HSD). Newly weaned male Wistar rats were fed either a standard chow diet or an isocaloric HSD for 18 weeks. Livers were harvested for histological, oxidative stress, gene expression, and lipidomic analyses. Intake of HSD increased oxidative stress and induced severe liver injury, microvesicular steatosis, and ballooning degeneration of hepatocytes. Using untargeted lipidomics, we identified and quantified 362 lipid species in the liver. Rats fed with HSD displayed increased hepatic levels of triacylglycerol enriched in saturated and monounsaturated fatty acids, lipids related to mitochondrial function/structure (phosphatidylglycerol, cardiolipin, and ubiquinone), and acylcarnitine (an intermediate lipid of fatty acid beta-oxidation). HSD-fed animals also presented increased levels of some species of membrane lipids and a decreased content of phospholipids containing omega-6 fatty acids. These changes in the lipidome were associated with the downregulation of genes involved in fatty acid oxidation in the liver. In conclusion, our data suggest that the chronic intake of a HSD, even under isocaloric conditions, induces lipid overload, and inefficient/impaired fatty acid oxidation in the liver. Such events lead to marked disturbance in hepatic lipid metabolism and the development of NAFLD. |
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