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How an experimental drug reverses fatty liver disease

Promising treatment in clinical trials has double action against triglyceride and fatty acid synthesis, UTSW study shows

Deep distilling
This illustration shows how an experimental drug that inhibits the DGAT2 enzyme reduces liver fat. Inhibition blocks the final step in triglyceride synthesis, which prevents the formation of new liver fat but also leads to an accumulation of phosphatidylethanolamine (PE) in the endoplasmic reticulum (ER) of cells. This accumulation blocks the activation of SREBP-1, the transcription factor that activates all genes involved in making fatty acids, leading to lower rates of new fat synthesis.

DALLAS – Feb. 28, 2024 – A drug in clinical trials as a treatment for metabolic dysfunction-associated steatotic liver disease (MASLD) works with a one-two punch that shuts down triglyceride production and fatty acid synthesis in liver cells, UT Southwestern Medical Center researchers show in a new study. Their findings, published in Cell Metabolism, shed light not only on the mechanism behind this experimental drug but also on how the body normally regulates triglyceride and fatty acid production.

Jay Horton, M.D.
Jay Horton, M.D., Professor of Internal Medicine, is Director of the Center for Human Nutrition and Director of the Nutrition Obesity Research Center at UT Southwestern. He holds the Distinguished University Chair in Human Nutrition, the Center for Human Nutrition Director's Endowed Chair, and the Scott Grundy Director's Chair.

“We’ve uncovered a new fundamental mechanism of regulation of fat synthesis in the liver,” said study leader Jay Horton, M.D., Professor of Internal Medicine in the Division of Digestive and Liver Diseases and Director of the Center for Human Nutrition at UT Southwestern. He also serves as Director of the Nutrition Obesity Research Center at UTSW, one of 12 such centers nationwide funded by the National Institutes of Health.

An estimated 25% of the world’s population has MASLD, a condition formerly known as nonalcoholic fatty liver disease that is characterized by a buildup of fat in the liver not associated with alcohol consumption. Over time, this excess fat causes inflammation and tissue damage that can lead to cirrhosis, liver failure that necessitates a transplant, or hepatocellular carcinoma, a form of liver cancer.

Although the cause of MASLD is not yet known, it is highly linked with obesity and insulin resistance, which have risen steadily worldwide in recent decades. The only effective treatment is weight loss, which can be difficult for many patients to achieve. There is currently no U.S. Food and Drug Administration-approved drug to treat the condition.

An experimental drug that inhibits an enzyme called diacylglycerol acyltransferase 2 (DGAT2) has shown significant promise, reducing liver fat and improving liver function in phase two trials. This enzyme, produced mostly in the liver, has long been known to be needed to make triglycerides – a type of fat generated in cells and circulated in blood. But how inhibiting DGAT2 shrinks liver fat in MASLD was unknown.

To study its mechanism, Dr. Horton and his colleagues tested the DGAT2 inhibitor on laboratory mice and rats. As shown in previous studies, the inhibitor dramatically lowered liver triglyceride concentrations in those treated. However, the inhibitor also dramatically decreased the amount of a protein called sterol regulatory element binding protein 1 (SREBP-1), which regulates the expression of genes involved in fatty acid and triglyceride synthesis. In the early 1990s, UTSW researchers Michael Brown, M.D., and Joseph Goldstein, M.D. – who shared the 1985 Nobel Prize in Physiology or Medicine for their work furthering the understanding of cholesterol metabolism – discovered SREBPs, a family of proteins that regulate cholesterol and fatty acid synthesis.

Further experiments showed that the DGAT2 inhibitor blocked SREBP-1 activation, preventing it from migrating to the cell nucleus to regulate genes that are required to make fatty acids and triglycerides. The combined effect of stemming DGAT2’s role in triglyceride synthesis and blocking SREBP-1’s role in activating genes involved in fatty acid and triglyceride synthesis stops fat from depositing in the liver, reversing MASLD, Dr. Horton explained.

These findings explain why the DGAT2 inhibitor has worked so well at treating MASLD in clinical trials as well as revealing a connection between DGAT2 and SREBP-1, Dr. Horton said. He added that this drug could be especially beneficial in patients carrying a mutated form of a gene called PNPLA3.

Through the Dallas Heart Study, founded in 2000, UTSW researchers Helen Hobbs, M.D., and Jonathan Cohen, Ph.D., discovered that a mutation in PNPLA3 significantly raises the risk of the most severe form of MASLD. SREBP-1 is the only known activator of this gene; consequently, deactivating it by inhibiting DGAT2 could also shut down PNPLA3, potentially preventing severe MASLD in patients who carry this mutation. 

The DGAT2 inhibitor is expected to begin phase three trials in the near future, bringing it closer to clinical use.

Other UTSW researchers who contributed to this study include first author Shunxing Rong, Ph.D., Goncalo Dias do Vale, Ph.D., and Chai-Wan Kim, Ph.D., Assistant Professors of Molecular Genetics and in the Center for Human Nutrition; Jeffrey McDonald, Ph.D., Professor of Molecular Genetics and in the Center for Human Nutrition; Arun Radhakrishnan, Ph.D., Professor of Molecular Genetics; Simeng Wang, M.D., Ph.D., Clinical Fellow in Digestive and Liver Diseases; and Shili Li, Ph.D., Research Scientist.

Dr. Brown, a Regental Professor, holds The W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research, and the Paul J. Thomas Chair in Medicine. Dr. Cohen holds the C. Vincent Prothro Distinguished Chair in Human Nutrition Research. Dr. Goldstein, a Regental Professor, holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research, and the Paul J. Thomas Chair in Medicine. Dr. Hobbs holds the Philip O’Bryan Montgomery, Jr., M.D., Distinguished Chair in Developmental Biology, the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development, and the 1995 Dallas Heart Ball Chair in Cardiology Research. Dr. Horton holds the Distinguished University Chair in Human Nutrition, the Center for Human Nutrition Director’s Endowed Chair, and the Scott Grundy Director’s Chair.

This study was funded by grants from the National Institutes of Health (P01HL-160487, P30DK127984, UL1TR003163, and AI-158357), The Welch Foundation (I-1793), and the Leducq Foundation (19CVD04). 

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.