A Proteomic-Based Characterization of Liver Metabolism

My thesis deals with studies on liver metabolism in the cow and pig, where the pig represents a potential human model for studying liver fat accumulation. In Study I, changes in liver metabolism between early lactation dairy cows with a low or high liver fat content was investigated, whereas the liver response in young pigs to a high-fat diet and diet restriction was investigated in Study II. The liver metabolism was studied using proteome analysis to allow simultaneous detection and quantification of a large number of proteins involved in metabolic pathways.

Study I: Liver protein expression in dairy cows with high liver triglycerides in early lactation

Fatty liver is a frequent subclinical health disorder in dairy cows, but the impact of fat accumulation on metabolic pathways in the liver is still unclear. Furthermore, at present, fatty liver can be detected reliably only by using liver biopsy. The objective was, therefore, to characterize quantitative differences in the liver proteome between early lactation dairy cows with a low or high liver fat content and suggest potential blood-based biomarkers for early detection of fatty liver. The liver proteome analysis indicated that a high liver fat content in early lactation is associated with increased oxidation of saturated fatty acids, oxidative stress, urea synthesis, and gluconeogenesis and decreased oxidation of unsaturated fatty acids. Based on correlations between liver proteins and plasma components, it is suggested that future studies investigate the sensitivity and specificity of plasma aspartate aminotransferase, ß-hydroxybutyrate, total bilirubin, total bile acids, and γ-glutamyltransferase for potential use as blood-based biomarkers for early detection of fatty liver in dairy cows. This study is the first to study the proteome of dairy cows with naturally occurring fatty liver in early lactation.

Study II: Liver protein expression in young pigs in response to a high-fat diet and diet restriction

Non-alcoholic fatty liver disease is a highly prevalent complication of childhood obesity characterized by an increased accumulation of liver lipids. However, the events responsible for liver lipid accumulation are poorly understood because human liver samples are rarely obtained. A suitable animal model may thus improve our understanding of liver lipid accumulation and contribute to the development of drugs. Although weight loss ultimately reduces liver lipid content, both a high-fat diet and diet restriction increase liver lipid accumulation in humans. The objective was, therefore, to investigate whether young pigs can be used to model the liver response in adolescents to a high-fat diet and diet restriction-induced weight loss. The results show that the liver response to increased fat intake and diet restriction displays similarities between pigs and humans. In contrast to humans, our results indicate that young pigs are resistant to fat-induced liver fat accumulation, whereas diet restriction decreases fatty acid oxidation and the subsequent ketogenesis in the liver. Consequently, the liver response in adolescents to a high-fat diet and diet restriction-induced weight loss cannot reliably be reproduced in young pigs.

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