Decoding the mysteries of metabolic disease: Meet UCLA’s Dr. Rajat Singh

Dr. Singh studies autophagy and mitochondrial health to find solutions for liver disease.
body with liver highlighted

A high-sugar diet is a known contributor to Type 2 diabetes, heart disease, and some cancers. But obesity’s impact on the liver, and the cascading effect it ignites, has received far less public attention, according to Rajat Singh, MD, director of the Liver Basic Science Research Program at UCLA.

In addition to over 500 vital functions, the liver is responsible for removing excess glucose from the bloodstream and storing it as glycogen. Eating a diet high in saturated fat, sugar, and simple carbohydrates (in addition to other lifestyle and genetic factors) prevents the liver from breaking food down and processing it as it normally should. Instead, it stores the glucose as fat.

Eventually, that fat build-up can lead to non-alcoholic fatty liver disease, or steatohepatitis — a condition you may have never heard of that affects an estimated quarter of the global population. Sometimes referred to as a “silent epidemic,” the disease progresses slowly, with few initial symptoms or biomarkers.

“When the liver can’t process fat, it will throw it back into the bloodstream,” says Dr. Singh, who joined the UCLA Department of Medicine in 2022. “Fatty liver disease sets the stage for cardiovascular disease, cancer and maybe even some neurodegeneration.”

In the Singh Lab, researchers believe that understanding how the body regulates lipid and energy metabolism — as well as the ways in which behaviors and medications could strengthen that process — may offer a solution for combating liver disease, diabetes and even aging.

One process they are particularly interested in studying is a “cellular recycling program” called autophagy. While old and damaged parts can prevent a cell from functioning properly, autophagy takes that cellular “trash” and repurposes it into new, usable parts.

“This is a really amazing quality control mechanism,” Dr. Singh says. “The longer you have it, the better, healthier, and longer you’re going to live.”

Uncovering the benefits of fasting

In 2009, Dr. Singh and colleagues at Albert Einstein College of Medicine in New York were the first to discover a previously unknown interrelationship between autophagy and lipid metabolism: As they describe in a Nature paper, autophagy mobilizes and degrades fat-stores (or lipids) in the liver — a process the researchers coined “lipophagy” — in order to regulate cell physiology and pathology.

It was an important discovery for the field, and 3,500 articles have since shown the existence of lipophagy in diverse cell types. The groundbreaking study also set the stage for Dr. Singh’s career in basic science research.

Prior to setting up a research program in the United States, Dr. Singh attended medical school in India. Fresh out of training and working in the Emergency Department, he encountered patients with heart attacks, strokes and snake bites. However, he soon realized he was far more interested in studying disease in the lab than treating patients in the clinic.

He went on to receive post-medical training in biochemistry and moved to the Bronx to study the underlying mechanisms of liver disease. It was a colleague, Ana Maria Cuervo, MD, PhD, at Albert Einstein, who introduced Dr. Singh to autophagy and sparked a lifelong interest in studying the cell process.

After the seminal Nature paper was published in 2009, Dr. Singh set up his own research program to investigate methods for inducing autophagy through natural and pharmaceutical means.

His group eventually uncovered one simple but surprising answer: intermittent fasting.

In a preclinical study, the researchers divided mice into two groups. While both groups received the exact same type and amount of calories per day, they were fed on different schedules: The intermittent fasting groups were fed between 8 and 10 a.m., and 5 and 7 p.m., while the control group had access to food all the time.

Findings from the study, published in Cell Metabolism in 2017, showed that consuming two meals per day, with complete food restriction between meals, did indeed induce autophagy. The mice on the intermittent fasting schedule experienced improved muscle mass, lower blood glucose levels, and lower lipid levels in the liver when compared to controls.

“A simple dietary change could activate the body’s cleansing system to help to prevent many of the devastating effects of obesity,” Dr. Singh says.

Understanding mitochondrial health

While continuing to explore this finding, Dr. Singh also began investigating the role of mammalian target of rapamycin (mTOR), a signaling mechanism that helps the body to build muscle.

While mTOR is activated during feeding, it is also activated during fasting — a paradox that Dr. Singh wanted to dig further into.

In his lab’s most recent study, published in Nature Cell Biology in June 2023, the researchers used genetic approaches to deactivate mTOR complex 2 in mice and compare the results to healthy controls. What they found was surprising.

“Autophagy wasn’t being changed in a way that would excite us, which means it probably wasn’t being controlled by this protein,” Dr. Singh says. “What we began to see was massive changes in mitochondria.”

With the mTOR complex 2 signaling turned off, the mitochondria had ballooned into long, massive “potato-like” structures that were preventing the cells from using oxygen efficiently.

“The fatty acids were doing something to control mitochondrial behavior,” Dr. Singh says. “Gradually, we began to develop a story that during fasting, the mitochondria need to be remodeled in a particular matter.”

While mTORC1 and mTORC2 both play central roles in cell metabolism, their functions are different. mTORC1 regulates protein synthesis in the cell, proliferation and growth, while mTORC2 is thought to regulate metabolism.

“Too much mTORC1 leads to cancers, metabolic diseases, and has a tendency to be hyper-activated with obesity and aging,” Dr. Singh says.

When the immunosuppressive drug rapamycin is given to patients (usually following a transplant), its primary role is to suppress mTORC1, which is sensitive to the drug. However, it can also start to suppress mTORC2. The findings from Dr. Singh’s study suggests that by suppressing mTORC2, mitochondrial health is put in jeopardy.

Dr. Singh’s study also suggests that the mTORC2 pathway that is triggered by fasting becomes less sensitive in aging animal models.

“We think that this mechanism falls apart with age,” he says.

In future studies, Dr. Singh’s team plans to test this theory and find ways to activate the mTORC2 mechanism and restore mitochondrial health in older mice, and eventually, humans.

Ingredients to well-being

Dr. Singh credits his own research as one reason he was able to make healthy lifestyle changes, in addition to moving to Los Angeles in 2022 and away from the Bronx, which he says has some of “the best Italian food outside of Italy.”

“Pizza, pasta, bread — I was eating so many carbs,” Dr. Singh says. “So, I’ve just cut out all processed carbohydrates entirely.”

He also tries to eat two big meals per day, with fasting in between. And he sticks with an exercise routine. Still a New Yorker at heart, Dr. Singh does not own a car, and instead jogs the 20 minutes from his home to his laboratory. 

Beyond diet and exercise, Dr. Singh says the most important ingredient to his well-balanced life is his first love, music. He built a music studio in his L.A. home and plays instruments daily – drums, guitar, and piano. Music is not only a hobby, but has had a positive effect on his work.

“Music gives me energy,” he says, “and it keeps me creative, which is a requirement for science.”

Lauren Ingeno is the author of this article.

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