Study title

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in modern society. Obesity, genetic variations and sex can play a role in determining the severity of the disease. Only a small fraction of genes accounting for NAFLD have been identified and etiology is largely unknown in the two sexes. There is no established therapy for NAFLD and knowledge is limited about the lipotoxic effects of different hepatic lipid species. I intend to examine the contribution of host genetics and sex hormones on diet-induced NAFLD and study the underlying molecular mechanisms in both sexes. I also intend to determine the lipotoxic effects of different hepatic lipid species using systems genetics. To identify novel genes related to the phenotype of interest, we have developed a high resolution mapping tool in mice: The Hybrid Mouse Diversity Panel (HMDP) including ~100 inbred strains of both sexes for which there is dense genotypic information. We study the genetic effects of diet-induced hepatic steatosis by feeding 8 weeks old HMDP mice a high-fat/high-sucrose diet for 8 weeks. We will measure hepatic lipids using a lipidomics approach and perform genome-wide association studies to identify genetic regions modulating the trait. Candidate genes will be validated in cell culture and in vivo mouse studies. To define the impact of sex hormones on hepatic lipids we will utilize samples collected from a study on male and female mice, which have undergone gonadectomy. Our preliminary genetic screen using HMDP unraveled a genome wide significant locus on chromosome 7 associated with hepatic TG accumulation in males. We also have data showing a strong protective effect of estrogen against adiposity as well as insulin resistance. More knowledge about factors contributing to NAFLD may be used for lifestyle intervention, when designing new drugs, or as diagnostic tools to identify subjects of both sexes at risk of developing this prevalent disease.