Zhao Zhang, Ph.D.
DALLAS – September 07, 2022 – Using a genetic screening platform developed by a UT Southwestern Nobel laureate, scientists from the Center for the Genetics of Host Defense at UT Southwestern Medical Center have identified genetic mutations that contribute to non-alcoholic fatty liver disease (NAFLD)providing a potential future target for therapeutic interventions.
While obesity and diabetes are well-known risk factors for fatty liver disease, researchers at UT Southwestern were able to identify a new cause of fatty liver disease in the absence of obesity – a reduced level of the gene predicted 4951 (gm4951), which in turn leads to non-alcoholic fatty liver disease. There are currently no approved drugs or treatments for this disease, which is rapidly becoming a major cause of chronic liver disease in the United States. Identifying the role of this gene in disease development provides an important new direction for those studying the disease to find potential treatments.
Bruce Beutler, Ph.D.
“We have identified a rare non-obese mouse model of NAFLD caused by GM4951 deficiency. This study lays the groundwork for the future development of approaches to activate the gm4951 counterpart to combat NAFLD,” said the lead author Zhao Zhang, Ph.D., Assistant Professor in the Center for Host Defense Genetics and the Division of Internal Medicine Endocrinology. The findings appear in Nature Communication.
The Host Defense Genetics Center is led by Bruce Beutler, Ph.D., Professor Regental and one of four Nobel Laureates at UT Southwestern. Dr. Beutler was awarded the 2011 Nobel Prize in Physiology or Medicine for discovering an important family of receptors that allow mammals to detect infections when they arise, triggering a powerful inflammatory response. Dr. Beutler has also developed the largest mouse mutagenesis program in the world, as well as an advanced genetic screening platform that allows Center researchers to screen for more than half of all genes in the mouse genome. In addition to a means of instantly identifying the mutations responsible for quantitative and qualitative phenotypes, the program enables the rapid discovery of many new components of the immune system.
“This study identified a potential human homolog of mouse GM4951 and the interaction of GM4951 with another human NAFLD/NASH-associated protein HSD17B13, suggesting that the finding is likely conserved in humans,” said Dr. Zhang. , whose laboratory is trying to understand the molecular mechanism. metabolic diseases, with the underlying aim of translating this knowledge into new therapeutic strategies.
The current study is based on the Advanced Genetic Screening Platform, which allowed researchers to identify two semi-dominant allelic missense mutations (oily and carboniferous) of gm4951 and define a critical role for GTPase-mediated translocation in hepatic lipid metabolism. Among their findings, the researchers found that loss of GM4951 causes NAFLD without obesity, GM4951 promotes lipid oxidation to prevent lipid accumulation in the liver, and GM4951 functions as a GTPase to translocate HSD17B13 into lipid droplets.
GM4951 is a poorly characterized protein, and this study defined GM4951’s role as a GTPase involved in lipid oxidation, Dr. Zhang said. GM4951-deficient mice developed nonalcoholic fatty liver disease on a high-fat diet with no changes in body weight or glucose metabolism, the researchers noted.
The research is supported by NIH grants R00DK115766 and R01DK130959 to Dr. Zhang; NIH grants R01AI125581 and U19AI100627 to Dr. Beutler; funding from the Lyda Hill Foundation to Dr. Beutler, and in part through a sponsored research agreement from Pfizer, Inc. to Dr. Beutler.
An estimated one-quarter of adults in the United States have non-alcoholic fatty liver disease (NAFLD), excess fat in liver cells that can cause chronic inflammation and liver damage, increasing the risk of liver cancer, d liver failure and requiring a transplant. NAFLD has become the most common cause of liver disease worldwide. Over the past few decades, it has been suggested that changes in lifestyles clearly drive the risk of NAFLD prevalence. However, liver fat content varies significantly between individuals with equivalent adiposity, indicating that genetic factors contribute to the development of NAFLD. Dr. Zhang’s lab is studying more than 20 genes in which mutations affect liver triglycerides without changes in body weight to identify new mechanisms of NAFLD.
UT Southwestern has several lines of research into the unknown causes of non-alcoholic fatty liver disease as well as potential treatments. Among them:
- A groundbreaking 2008 study by Drs. Helen Hobbs and Jonathan Cohen, who run a joint lab at the Eugene McDermott Center for Human Growth and Development, came from the Dallas Heart Study and discovered a genetic basis for the risk of developing NAFLD. The study found that a variation in the PNPLA3 gene may make people more likely to develop fatty liver disease and progress to NAFLD, and while the troublesome gene variant is rare among African Americans, nearly half of Hispanics have it. The results reflected and helped explain clinically observed differences in NAFLD between these two groups. In 2017, the two reported how obesity significantly amplifies the effects of three genetic variants that increase the risk of nonalcoholic fatty liver disease through different metabolic pathways.
- Investigations by Dr. Jay Horton, director of the Center for Human Nutrition at UT Southwestern, showed that removing a protein known as Scap reduced fat production and prevented fatty liver disease in mice despite obesity, high fat diets and hyperglycemia. This happened, Dr. Horton reported, because without Scap, the mice could not make the SREBPs involved in lipid manufacturing and storage. He later reported that liver fat can be reduced in humans with fatty liver disease by inhibiting two enzymes involved in the manufacture of fatty acids – acetyl-CoA carboxylase 1 and 2. Although this inhibition is associated with a increased levels of triglycerides in the blood, there are ways to prevent or treat this condition.
- UT Southwestern researchers in the division of liver and digestive diseases have been involved in clinical trials evaluating potential pharmaceuticals like Emricasan, an anti-inflammatory drug with fast-track FDA designation for the treatment of non-alcoholic steatohepatitis cirrhosis. TARGET-NASH is a longitudinal observational cohort study of patients cared for for NASH and related conditions across the NAFLD spectrum in routine clinical practice. TARGET-NASH is a research registry of patients with NAFL or NASH in real-life academic and community-based practice settings to assess the safety and effectiveness of current and future therapies.
- Scientists at UT Southwestern’s Division of Digestive and Liver Diseases and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center recently developed a simple blood test to predict which NAFLD patients are most likely to develop a liver cancer. Studies have shown that people with NAFLD have an up to 17 times higher risk of liver cancer. For NAFLD patients considered most at risk for cancer, doctors recommend a demanding screening program involving liver ultrasound every six months. But identifying patients who belong to this group is difficult and usually involves invasive biopsies.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 researchers from the Howard Hughes Medical Institute. Full-time faculty of more than 2,900 are responsible for groundbreaking medical advances and committed to rapidly translating scientific research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 inpatients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits annually.