Abstract
Pharmacological treatment modalities for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are scarce, and discoveries are challenged by lack of predictive animal models adequately reflecting severe human disease stages and co-morbidities such as obesity and type 2 diabetes. To mimic human NAFLD/NASH etiology, many preclinical models rely on specific dietary components, though metabolism may differ considerably between species, potentially affecting outcomes and limiting comparability between studies. Consequently, understanding the physiological effects of dietary components is critical for high translational validity. This study investigated the effects of high fat, cholesterol, and carbohydrate sources on NASH development and metabolic outcomes in guinea pigs. Diet groups (n = 8/group) included: low-fat low-starch (LF-LSt), low-fat high-starch (LF-HSt), high-fat (HF) or HF with 4.2%, or 8.4% sugar water supplementation. The results showed that caloric compensation in HF animals supplied with sugar water led to reduced feed intake and a milder NASH phenotype compared to HF. The HF group displayed advanced NASH, weight gain and glucose intolerance compared to LF-LSt animals, but not LF-HSt, indicating an undesirable effect of starch in the control diet. Our findings support the HF guinea pig as a model of advanced NASH and highlights the importance in considering carbohydrate sources in preclinical studies of NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) and the more advanced form steatohepatitis (NASH) are multifactorial and progressive diseases, and in humans are often accompanied by comorbidities such as obesity, insulin resistance and dyslipidemia [1]
This is corroborated by several studies in humans that have shown a link between soft drink consumption and obesity, insulin resistance and NAFLD [11,12,13,14]
Considering the lower energy content as well as the higher amount of refined sugar in the high fat diet, the current study explored if insulin resistance could be induced by HFCS supplements in the drinking water while ensuring comparison to a low-calorie low-starch control group (LF-LSt, 11.2 MJ/kg)
Summary
Non-alcoholic fatty liver disease (NAFLD) and the more advanced form steatohepatitis (NASH) are multifactorial and progressive diseases, and in humans are often accompanied by comorbidities such as obesity, insulin resistance and dyslipidemia [1]. The deposition of surplus fat in hepatocytes (hepatic steatosis) represents the initial hallmark of the disease and is accelerated by an excessive energy consumption This is in line with the association with obesity and metabolic dysfunction reported for many human patients and commonly linked to a diet rich in fat, cholesterol and carbohydrates [3,4]. Soft drink consumption has a limited effect on overall satiety often resulting in additional caloric intake and subsequent ‘energy-overload’ in turn promoting metabolic stress [9,10] This is corroborated by several studies in humans that have shown a link between soft drink consumption and obesity, insulin resistance and NAFLD [11,12,13,14]. The addition of a fructose/corn-syrup based ‘soft drink component’ to a high fat diet has been shown to accelerate NAFLD/NASH in some experimental animal models, promoting the use of HFCS in preclinical disease modeling [15,16,17,18,19,20]
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