Date of Completion

8-23-2013

Embargo Period

8-23-2014

Keywords

Non-alcoholic fatty liver disease, cholesterol, guinea pigs, hepatic lipid metabolism

Major Advisor

Dr. Jeff S Volek

Co-Major Advisor

Dr. Maria-Luz Fernandez

Associate Advisor

Dr. Sung I Koo

Associate Advisor

Dr. Hedley C Freake

Field of Study

Nutritional Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological entity that includes a spectrum of histological and biochemical anomalies. NAFLD begins with excessive lipid accumulation within hepatocytes (hepatic steatosis) and can transition to non-alcoholic steatohepatitis (NASH), characterized by hepatic inflammation and injury that can render the liver vulnerable to bridging fibrosis, cirrhosis, and hepatocellular carcinoma. Dietary cholesterol has been proposed as a potential mediator of the transition from steatosis to NASH. Guinea pigs are similar to humans in terms of hepatic cholesterol metabolism and were implemented in three studies to explore its contribution to NAFLD. In study one male guinea pigs (n = 10/group) were randomly assigned to either a 0.25% high-cholesterol (H-Chol) or a 0.04% low-cholesterol diet (L-Chol) for six weeks. H-Chol feeding promoted weight loss (p = 0.0009), hypercholesterolemia, elevated plasma alanine and aspartate aminotransferases (p = 0.042, p = 0.049 respectively), and accumulation of total hepatic cholesterol (p < 0.0001) and triglyceride (p = 0.002). H-Chol livers developed moderate steatosis along with evidence of mild inflammation and injury. Therefore, these results support the participation of increased dietary cholesterol in promoting NAFLD. Macronutrient composition also influences NAFLD, therefore study two sought to determine the impact of feeding a diet low in carbohydrate and high in fat (LCD; n = 9) or a high carbohydrate diet (HCD; n = 10) to guinea pigs with cholesterol-induced NAFLD. Both groups failed to improve liver histology despite greater lipid accumulation in LCD livers. Biochemical liver injury was similar between groups, suggesting that both LCD and HCD are unable to improve cholesterol-mediated NAFLD. Study three demonstrated that phospholipids (PL) and triglycerides from H-Chol livers had an increased unsaturated and decreased saturated fatty acid profile. H-Chol also significantly lowered levels of PL arachidonic acid (p = 0.004). There were no differences between LCD or HCD, however both had significant reductions in overall PL content (p = 0.001) and similar increases in unsaturated and decreases in saturated fatty acid in PL and triglyceride when compared to H-Chol. In conclusion, elevated dietary cholesterol participates in NAFLD development and impacts the effectiveness of dietary intervention in guinea pigs.

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