Helen Hobbs's research is focused on defining the molecular basis of metabolic disorders and heart diseaae. She has used human genetics to identify mutations that cause elevated (or decreased) levels of lipids in tissues, and performed mechanistic studies to define the physiological roles and pathogenic mechanisms of the culprit proteins. Her work has provided insights into cholesterol and triglyceride metabolism and identified new drug targets for the prevention of atherosclerotic heart disease.
Genetic Susceptibility to Fatty Liver Disease
A missense mutation in PNPLA3, a gene expressed in adipose tissue and liver, is associated with nonalcoholic fatty liver disease (NAFLD). Substitution of methionine for isoleucine at amino acid 148 is associated not only with an increased amount of fat in the liver (hepatic steatosis) but also with inflammation (nonalcoholic steatohepatitis) and fibrosis (cirrhosis) in humans. Moreover, the same sequence variation is also associated with alcoholic cirrhosis. Alcoholics who are homozygous for this variant have a 4-fold greater risk of developing cirrhosis than those who do not have a risk allele.
We have developed a genetically modified mouse model that recapitulates the increase in hepatic triglyceride in association with expression of the PNPLA3 variant. We are now using a variety of approaches to determine why expression of this variant in PNPLA3 in the liver causes hepatic steatosis and associated inflammation. Here we will determine if the accumulation of excess triglyceride in the mice is caused by an increase in synthesis of triglyceride by the liver, a decrease in oxidation of fatty acids, or reduced secretion of triglyceride as lipoproteins. Experiments to address these questions will be conducted by measuring and comparing these parameters in mice expressing the mutant form of PNPLA3 and in control mice using established protocols.
In this project you would learn how to maintain a colony of mice, handle mice, isolate hepatocytes from mice and rats, and perform experiments to assess fatty acid metabolism in both cultured cells and in vivo.