High-fat but not sucrose intake is essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea p

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RESEARCH

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High-fat but not sucrose intake is essential for induction of dyslipidemia and nonalcoholic steatohepatitis in guinea pigs David Højland Ipsen1, Pernille Tveden-Nyborg1, Bidda Rolin2, Günaj Rakipovski2, Maria Beck1, Line Winther Mortensen1, Lasse Færk1, Peter Mikael Helweg Heegaard3, Peter Møller4 and Jens Lykkesfeldt1*

Abstract Background: Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat/cholesterol on the development of dyslipidemia and NAFLD. Methods: Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0. 35 % cholesterol), a high-fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. Results: All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p < 0.0001), LDL-C (p < 0.0001) and VLDL-C (p < 0.05) compared to control and vHS. Contrary to this, plasma triglycerides were increased in control and vHS compared to high-fat fed animals (p < 0.01), while circulating levels of free fatty acids were even between groups. Histological evaluation of liver sections revealed nonalcoholic steatohepatitis (NASH) with progressive inflammation and bridging fibrosis in high-fat fed animals. Accordingly, hepatic triglycerides (p < 0.05) and cholesterol (p < 0.0001) was increased alongside elevated levels of alanine and aspartate aminotransferase (p < 0.01) compared to control and vHS. Conclusion: Collectively, our results suggest that intake of fat and cholesterol, but not sucrose, are the main factors driving the development and progression of dyslipidemia and NAFLD/NASH. Keywords: Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Dyslipidemia, High-fat diet, Sucrose, Guinea pigs, Cholesterol

Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world [1] and is closely associated with dyslipidemia [2, 3]. Affecting more than 30 % of the general adult population and with the potential to progress from simple steatosis to irreversible and life-threatening non-alcoholic steatohepatitis (NASH), it is an important public health * Correspondence: [email protected] 1 Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark Full list of author information is available at the end of the article

concern [1, 4]. Disease progression is instigated by a series of parallel hits such as inflammation and oxidative stress, causing hepatocyte damage (e.g. metabolic dysfunction, DNA injury and apop