The liver is emerging as an underexplored nexus of metabolic dysfunction in diabetes, as metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular (CV) risk are linked through multiple lipoprotein pathways in obesity and diabetes.

“When we target lipoproteins, we are often marking our measures of health with some of the most benign lipids out there, triglycerides,” said Scott Summers, PhD, Distinguished Professor and Chair of Nutrition and Integrative Physiology, and the William J. Rutter, PhD, Presidential Endowed Chair of Biochemistry at the Eccles Institute of Human Genetics, University of Utah. “I’m not even sure cholesterol itself is really the main driver of risk. Lipoproteins carry a lot with them, and we are just starting to dissect the parts of those complex structures that are really doing the damage.”

Dr. Summers will explore the role of ceramides in MASLD and CV risk during a symposium offering early answers to How Does MASLD Impact Lipoprotein Biology and Cardiovascular Risk with Obesity and Diabetes? on Monday, June 8 from 3:15–4:15 p.m. in room R05 of the Ernest N. Morial Convention Center. On-demand access to recorded presentations will be available to registered participants following the conclusion of the Scientific Sessions, from June 10–August 10.

Ze Zheng, MD, PhD, Associate Professor of Medicine and Associate Director of Cardiovascular Research Center at the Medical College of Wisconsin, and Investigator at Versiti Blood Research Institute, will address the latest findings linking very low-density lipoprotein (VLDL) cholesterol, clot lysis, and thrombosis.

“People with obesity and diabetes have a higher risk of developing thrombosis, a well-recognized phenomenon in the clinic,” Dr. Zheng said. “The underlying mechanism is not very clear, but the proteins involved in producing clots and also breaking down clots are mostly made in the liver.”

The liver is central to multiple metabolic processes, Dr. Zheng noted, not just clot formation and lysis. Obesity and diabetes, particularly type 2 diabetes, disrupt normal lipoprotein biology and contribute to MASLD, which can progress to cirrhosis and liver failure. Abnormal lipoprotein biology associated with MASLD, in turn, contributes to an elevated risk to the heart, kidney, and other organ systems.

Weight loss is an obvious approach to managing MASLD, CV risk, and other complications of diabetes, but weight loss remains an elusive target. Clinical research is needed to better characterize the associations between clot formation, lysis, and thrombosis in the setting of diabetes and obesity.

“Thrombosis is a huge problem for people with diabetes and one that patients and clinicians need to focus on,” Dr. Zheng said. “It’s not just two separate mechanisms that happen coincidentally. There are connections in the liver. Thrombotic conditions really do need preventive care.”

Picking the most clinically relevant lipoprotein cargo can be a puzzle. There are thousands of different lipids in these entities, Dr. Summers said, not all of them well understood or characterized. His research has focused on ceramides, which make up about 50% of the outermost layer of skin. While dermatologists and cosmetic manufacturers focus on the role of ceramides in maintaining the skin barrier, he has focused on ceramides in CV disease.

Ceramides are synthetized in the liver, cardiac, endovascular, and other tissues and transported in low-density lipoprotein (LDL) cholesterol.

“We think ceramides are really bad,” Dr. Summers said. “Ceramides are now being measured as a new way to stratify major adverse cardiac event risk. If we block ceramide production in a mouse, we can make a mouse that doesn’t get MASLD, doesn’t get insulin resistance and diabetes, doesn’t get heart failure, and doesn’t get kidney disease. It’s clear that ceramides can be pretty toxic.”

Whether ceramide synthesis in humans can also be pharmacologically targeted remains a question. An initial phase 1 clinical trial was recently completed with an investigative agent that alters one enzyme in ceramide synthesis, making ceramides less sticky and less likely to bind to other lipids in liver, heart, and kidney tissue, without obvious adverse effects on the skin. Ceramide synthesis associated with skin formation and maintenance uses different enzymes.

“It’s a different type of approach to lipoproteins, one that is more specific than just trying to get rid of all the fat in the bloodstream, which is unrealistic and probably not going to happen in the general population,” Dr. Summers said. “We think we can target ceramides without having a huge skin effect. The question is, can we really do that in a person long term? We hope we can.”

Also during this session, W. Timothy Garvey, MD, Professor of Nutrition Science at the University of Alabama at Birmingham (UAB) and Director of the UAB Diabetes Research Center, will discuss growing evidence that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce CV risk by improving fatty liver.

Save the date

Make plans to join us June 18–21, 2027, for the 2027 Scientific Sessions at the Walter E. Washington Convention Center in Washington, DC. Registration will open in January.