Contribution of de novo lipogenesis to the progression of nonalcoholic fatty liver disease

Abstract

This dissertation is focused on understanding the biochemical pathway of de novo lipogenesis (DNL) in humans and how changes in DNL can alter disease states, particularly nonalcoholic fatty liver disease (NAFLD). This document's first chapter presents a review of the literature, while the second chapter focuses on investigating the contribution of DNL to the progression of NAFLD. The main outcome of this study was that as disease severity progressed, hepatic DNL increased in a stepwise fashion until fibrosis was significant, at which time DNL was found to be reduced. Conclusions from isotopic labeling of liver were mirrored by data from protein and gene expression studies which pointed toward mechanisms of promoting both fat storage and decreased fatty acid oxidation. In the third chapter, data are presented on the effects of pharmacological inhibition of DNL, which lowered both liver fat (from 11.8 [percent] to 10.3 [percent]) and liver enzymes (from 29 to 22 U/L). In this study, different subjects received different doses (50, 100, and 15 mg/d) and within the high dose group, DNL was reduced maximally by 75 [percent] which resulted in a 5 [percent] reduction in liver fat and a 36 [percent] reduction in liver enzymes. Lastly, this dissertation's fourth chapter presents data from an investigation in which acute overconsumption of food and alcohol increased liver fat only in individuals whose DNL was stimulated by this treatment but not in individuals with unchanged DNL. The variability in response between subjects was surprising and suggested that for some people, overconsumption of carbohydrates may have greater lipogenic effects than excess alcohol. Future studies should identify the factors that govern this response. In summary, the combined data from these studies highlight the significance of the DNL pathway in promoting increased fat storage in the liver. This conclusion is supported by independent observations of both the negative effects of increased DNL on the liver and the benefits of reducing flux through this pathway to improve liver health. Both dietary and pharmacologic approaches to reduce DNL should be the focus of future treatment of NAFLD.