US Southwestern University geneticists have identified a new mechanism of nonalcoholic fatty liver disease in the absence of obesity: newsroom

Zhao Chang, Ph.D.

DALLAS – September 7, 2022 – Using a genetic screening platform developed by the Nobel laureate in southwestern Utah, scientists at the Center for Host Defense Genetics at the University of Texas 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, US Southwestern University researchers were able to identify a new cause of fatty liver disease in the absence of obesity – a decrease in the level of the predicted gene 4951 (EGP 4951), which in turn leads to non-alcoholic fatty liver disease. There are currently no approved medications or treatments for this disease, which is rapidly emerging as a leading cause of chronic liver disease in the United States. Defining the role of this gene in disease progression provides an important new direction for those studying the disease to find potential treatments.

Bruce Butler, Ph.D.

“We identified a rare non-obese mouse model of NAFLD due to GM4951 deficiency. This study lays the foundation for future development of human activation approaches. EGP 4951 symmetric anti-NAFLD,” the lead author said Zhao Chang, Ph.D., Assistant Professor in the Center for Host Defense Genetics and the Department of Endocrinology in Internal Medicine. The results appear in Nature Communications.

The Host Defense Genetics Center directed by Bruce Butler, Ph.D.He is a Royal Professor and one of four UT Southwestern Nobel Laureates. Dr. Butler was awarded the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of receptors that allow mammals to sense infection when it occurs, triggering a potent inflammatory response. Dr. Bettler has also developed the world’s largest mouse mutagenesis program, along with a front-end genetic screen platform that allows researchers at the center to screen more than half of all genes in the mouse genome. Combined with the means of immediate identification of mutations responsible for quantitative and qualitative phenotypes, the program allows the rapid detection of many new components of the immune system.

Zhang, whose lab is working to understand the molecular mechanism of metabolic disease, said a primary goal is to translate this knowledge into new treatment strategies.

The current study was built on the forward genetic screen platform, which allowed the researchers to identify two semi-dominant (oil and carbon) allelic missense mutations from EGP 4951 and identifying 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, that GM4951 promotes lipid oxidation to prevent lipid accumulation in the liver, and that GM4951 acts as a GTPase to transport HSD17B13 into lipid droplets.

Dr. Zhang said GM4951 is a poorly characterized protein and this study identified the role of GM4951 as a GTPase involved in lipid oxidation. The researchers observed that GM4951-deficient mice developed nonalcoholic fatty liver disease on a high-fat diet with no change in body weight or glucose metabolism.

The research is supported by National Institutes of Health grants R00DK115766 and R01DK130959 to Dr. Chang. NIH awards R01AI125581 and U19AI100627 to Dr. Butler; Funded by Dr. Beutler’s Lyda Hill Foundation, and in part through a research agreement sponsored by Pfizer, Inc. To Dr. Beutler.

It is estimated that a quarter of adults in the United States have nonalcoholic fatty liver disease (NAFLD), an excess of fat in liver cells that can cause chronic inflammation and liver damage, increasing the risk of liver cancer, liver failure, and the need for transplant. NAFLD has become the most common cause of liver disease worldwide. In recent decades, it has been suggested that changes in lifestyles clearly lead to the risk of NAFLD spreading. However, hepatic lipid content varies greatly between individuals with equivalent lipids, suggesting that genetic factors contribute to the development of NAFLD. Dr. Zhang’s lab He studies more than 20 genes in which mutations affect triglycerides in the liver without altering body weight to identify novel mechanisms of NAFLD.

UT Southwestern has several lines of investigation into the unknown causes of nonalcoholic fatty liver disease as well as potential treatments. between them:

  • A pioneering study in 2008 by Dr. Helen Hobbs and Jonathan Cohen, who run a joint laboratory in Eugene McDermott Center for Human Growth and Development It originated from the Dallas Heart Study and discovered a genetic basis for the risk of NAFLD. The study found that a variation in the PNPLA3 gene can make people more likely to develop fatty liver and progress to NAFLD, and that while the troublesome gene variant is uncommon in African Americans, nearly half of Hispanics have it. The results reversed and helped explain the differences in NAFLD observed in the clinic between these two groups. In 2017, the two reported How obesity dramatically amplifies the effects of three genetic variants that increase the risk of nonalcoholic fatty liver disease through various metabolic pathways.
  • Dr. Jay Horton Investigations, Director UT Southwestern Center for Human Nutrition showed that deleting a protein known as SCAP reduces lipid production and prevents fatty liver disease in mice despite obesity, a high-fat diet, and high blood sugar. Dr. Horton stated that this occurred because without Scab, the mice could not make the SREBPs involved in lipid synthesis and storage. It was later reported that liver fat could be reduced in humans with fatty liver by inhibiting two enzymes involved in making fatty acids – acetyl-CoA carboxylase 1 and 2. While this inhibition has been associated with increased levels of triglycerides in the blood, there are ways to prevent it . or treat this condition.
  • US Southwestern University researchers in the Division of Hepatology and Gastroenterology participated in Clinical trials to evaluate potential drugs Like Emricasan, an anti-inflammatory drug with fast-track designation by the US Food and Drug Administration for the treatment of nonalcoholic fatty liver cirrhosis. TARGET-NASH is a longitudinal observational cohort study of patients managed for NASH and related conditions across the full spectrum of NAFLD in standard clinical practice. TARGET-NASH is a research registry of patients with NAFL or NASH within real-world academic and community practices maintained in order to evaluate the safety and efficacy of current and future treatments.
  • UT Southwestern scientists in the Division of Gastroenterology and Hepatology and the Harold C. Simmons Comprehensive Cancer Center of the University of Southwestern recently recently Simple blood test To predict patients with non-alcoholic fatty liver at increased risk of developing liver cancer. Studies have found that people with NAFLD have up to 17 times the risk of developing liver cancer. For NAFLD patients who are thought to be at higher risk of developing cancer, doctors recommend a demanding screening program that includes a liver ultrasound every six months. But identifying patients in this group is challenging and has usually involved invasive biopsies.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s leading academic medical centers, combines groundbreaking 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 investigators of the Howard Hughes Medical Institute. Our 2,900-plus full-time faculty are responsible for pioneering medical developments and are committed to quickly translating scientific research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties for more than 100,000 hospital patients, more than 360,000 emergencies, and oversee nearly 4 million outpatient visits annually.

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