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The coming epidemic?

Fatty liver tissue
Fatty liver tissue

When Jay Horton was finishing medical school at the University of Iowa in the 1980s and looking for a place to do his residency, UT Southwestern Medical Center should have seemed the perfect choice. After all, he wanted to train somewhere warmer than Iowa – and the right spot to continue his cholesterol research.

Drs. Michael Brown and Joseph Goldstein had just won the Nobel Prize for their discoveries involving cholesterol metabolism in 1985, and Dallas is certainly warm.

Still, the Texas institution never crossed his mind. “When my mentor suggested UT Southwestern, I actually said, ‘Who are Brown and Goldstein?’”

Dr. Jay Horton
Dr. Jay Horton

But after doing some research, he wisely took his mentor’s advice. In 1995, following an internal medicine residency and gastroenterology fellowship at UT Southwestern, Dr. Horton began working in the lab of the famed Nobel Laureates as a Howard Hughes Medical Institute postdoctoral fellow, studying transcriptional regulation of cholesterol.

Now, after a quarter-century in Texas, Dr. Horton is Director of the Center for Human Nutrition and a Professor of Internal Medicine and Molecular Genetics at UT Southwestern, one of the world’s leading research institutions for examining the mechanisms and genetics behind what is becoming a major international health problem – nonalcoholic fatty liver disease, or NAFLD.

Emerging threat

About a third of all adults have NAFLD, according to findings of the Dallas Heart Study, UT Southwestern’s cardiovascular research project started in 2000 and involving more than 6,000 Dallas County participants. NAFLD is actually a range of related disorders.

Doctors now know that NAFLD can result from obesity and insulin resistance (the body’s failure to respond to insulin, resulting in high blood sugar levels) rather than from alcoholism.

The National Institutes of Health (NIH) estimates that 30 to 40 percent of U.S. adults have simple fatty liver, a buildup of fat in the liver without significant inflammation or cell damage. An estimated 3 to 12 percent of adults in the U.S. have a more serious form of NAFLD, called nonalcoholic steatohepatitis (NASH), a buildup of liver fat with inflammation and cell damage that can lead to cirrhosis. This stunning incidence rate is for a disease that was unrecognized 40 years ago.

A 1980 Mayo Clinic Proceedings study described NASH as “a previously unnamed liver disease that … mimics alcoholic hepatitis and that may also progress to cirrhosis.” Before that time, doctors thought a patient with a failing liver containing high levels of fat as well as the inflammation and scarring characteristic of late-stage fatty liver disease had that damage due to alcoholism, Dr. Horton says.

Doctors now know that NAFLD can result from obesity and insulin resistance (the body’s failure to respond to insulin, resulting in high blood sugar levels) rather than from alcoholism. “As the U.S. and the world have become fatter and more insulin-resistant, the disease has become more prominent,” Dr. Horton says.

In its early stages, a patient may notice few if any symptoms as excess fat quietly builds up in the liver. However, 15 to 20 percent of patients will go on to develop NASH with liver inflammation and increasing liver damage, he says.

Among NASH patients, an estimated 15 to 20 percent will then develop cirrhosis of the liver, with fibrosis making the liver hard and the organ eventually failing, Dr. Horton says.

Stages of liver damage

By this stage, patients often have abdominal pain, swelling, and jaundice as the liver loses its ability to metabolize sugars and proteins. “Without a functioning liver, you can’t regulate your blood glucose levels, so you essentially die of low blood sugar,” Dr. Horton says. NAFLD also increases the risk of heart disease, which the NIH says is the cause of death for most people with either form of NAFLD.

A liver transplant may be necessary to survive. In fact, with recent advances in the prevention and treatment of hepatitis C, nonalcoholic fatty liver disease is poised to displace that viral disease as the leading cause for such transplants, according to Dr. Horton. Another risk is liver cancer. Here, too, with hepatitis C becoming less of a threat, NAFLD is emerging as a leading cause of liver cancer.

Mentored by Nobelists

While working in the Brown-Goldstein lab, Dr. Horton developed a love for the thrill of discovery.

His name began appearing on studies alongside those of the Nobel Prize winners as the lab studied proteins involved in manufacturing and storing lipids called sterol regulatory element-binding proteins, or SREBPs.

Later, he collaborated with Dr. Helen Hobbs, Director of the Eugene McDermott Center for Human Growth and Development, and Dr. Jonathan Cohen, a Professor in the Center for Human Nutrition, the McDermott Center, and of Internal Medicine – who also run a joint laboratory. They identified mutations in the PCSK9 gene that result in low blood cholesterol levels and protect against heart disease. That research led to the development of a new class of drugs to lower cholesterol, the PCSK9 inhibitors.

Now, he says, the demon to conquer is NAFLD.

In a 2012 Cell Metabolism paper, Dr. Horton showed that deleting a protein known as Scap reduced fat production and prevented fatty liver disease in mice despite obesity, high-fat diets, and high blood sugar. This occurred, Dr. Horton reported, because without Scap, the mice could not make the SREBPs involved in lipid manufacture and storage.

In a 2017 Cell Metabolism paper, Dr. Horton reported that liver fat can be reduced in humans with fatty livers by inhibiting two enzymes involved in making fatty acids — acetyl-CoA carboxylase 1 and 2. While that inhibition was associated with increased triglyceride levels in the blood, there are ways to prevent or treat that condition, Dr. Horton says.

Dr. Horton’s research provides promise for the development of new treatments for NAFLD.

Building upon a foundation

Mass spectrometry laboratory
Mass spectrometry laboratory

Meanwhile, UT Southwestern’s Center for Human Nutrition is one of the world’s largest and most recognized centers for lipid and fatty liver research, with Dr. Horton’s own Molecular Genetics lab only one flank in the research assault underway across campus, he says.

Dr. Horton points to a groundbreaking 2008 study by Drs. Hobbs and Cohen that arose from the Dallas Heart Study and unearthed a genetic basis for the risk of developing NAFLD.

The study reported in Nature Genetics found that a variation in the PNPLA3 gene can make people more susceptible to developing fatty livers and progressing to NAFLD, and that while the troublesome gene variant is uncommon in African-Americans, almost half of Hispanics have it. The findings mirrored and helped explain the differences in NAFLD observed in the clinic between those two groups.

“We’ve made a lot of progress in understanding the molecular events in how fat accumulates and understanding the mutations of specific genes associated with this disease,” Dr. Horton says. “Now we want to know how and why this disease progresses.”

Dr. Brown, a Regental Professor, is Director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease, as well as a Professor of Molecular Genetics and Internal Medicine. He 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, is Chair of Molecular Genetics and a Professor of Molecular Genetics and Internal Medicine. He holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine.

Dr. Hobbs is a Professor of Internal Medicine and Molecular Genetics as well as a Howard Hughes Medical Institute Investigator. She 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 Chair in Human Nutrition, The Dr. Robert C. and Veronica Atkins Chair in Obesity & Diabetes Research, the Center for Human Nutrition Director’s Endowed Chair, and the Scott Grundy Director’s Chair.