Lefkowitz Distinguished Lecture explores how genes affect lipid levels.
Both cholesterol and triglycerides are essential lipids, but when they accumulate in our bodies, they cause diseases like heart disease and fatty liver disease. While diet and exercise are the most important factors, genes offer clues, too.
As part of Duke University School of Medicine’s second annual Research Week, Helen Hobbs MD, gave a talk called “Genetic Disorders of Dietary Excess,” in which she discussed the role that genes can play in the development of heart disease and fatty liver disease.
Hobbs, the 2020 Robert J. Lefkowitz, MD, Distinguished Lecturer, was introduced by Lefkowitz, James B. Duke Distinguished Professor of Medicine at Duke, and 2012 recipient of the Nobel Prize in Chemistry.
“Helen’s science is dazzling for its originality, its fundamental insights and for its clinical translation,” Lefkowitz said.
Having high LDL cholesterol, the so-called “bad cholesterol,” is enough to cause heart disease, said Hobbs, but she and her team use genetics to help clarify the relationship between cholesterol and disease. Using the Dallas Heart Study, a longitudinal, multiethnic, population-based study of Dallas County, of which Hobbs is the director, the team spotted a key gene: PCSK9.
PCSK9 breaks down LDL receptor proteins before they reach the cell surface, leaving more cholesterol behind in the blood stream. That cholesterol can then accumulate elsewhere in the body and cause disease.
A loss of function mutation in the PCSK9 gene, though, basically eliminates this cycle. People with this mutation have lower cumulative exposure of LDL cholesterol and greater protection against heart disease. This discovery created a new therapeutic target to treat patients with high cholesterol.
Like cholesterol, an excess of triglycerides can lead to disease, Hobbs said. Fatty liver disease happens when too much fat gets stored in the liver. As fat continues to accumulate, the condition can worsen into cirrhosis. Hobbs and team again used the Dallas Heart Study to find the prevalence of fatty liver disease. The team found two different genetic pathways that can cause fatty liver disease.
Using a genome wide association study, they found that a homozygous variant in the PNPLA3 gene is a strong risk factor for fatty liver disease but is heavily dependent on diet. According to Hobbs, a lean, healthy person with the homozygous variant of PNPLA3 will likely not contract fatty liver disease, but a person with obesity with that variant almost certainly will. Knowing that pathway opens up doors for targeted treatment to try to remove or mute that variant gene.
But PNPLA3 isn’t the only gene that can cause fatty liver disease. Hobbs also found that the TM6SF2 gene is implicated in an increased risk. Unlike PNPLA3, it is not regulated by food. Currently, Hobbs is conducting more research to better understand how TM6SF2 works
“The problem is the constant presence of triglycerides in the liver in some people is associated with inflammation and fibrosis,” Hobbs said.
This research points to future clinical interventions that could work to lower lipid levels and attack fatty liver disease.
Hobbs is a Howard Hughes Medical Institute (HHMI) Investigator and a professor of Internal Medicine and Molecular Genetics at the University of Texas Southwestern Medical Center. She is the director of the McDermott Center for Human Growth and Development and the Dallas Heart Study. She has accumulated several awards throughout her career including the Harrington Prize for Innovation in Medicine in 2018 and Breakthrough Prize in Life Sciences in 2016.