Research is uncovering significant information about the role of liver fat in metabolic function, with consequences that extend not only to liver disease but to obesity and diabetes as well.
During the Sunday afternoon symposium Liver Fat and Metabolic Function—Obesity, Gene, and Gut Interactions, four researchers will review the latest findings. The two-hour session begins at 4:30 p.m. in room 30.
“There’s very limited awareness among clinicians and diabetologists of the negative impact of hepatic fat, not only on metabolism in terms of promoting atherogenic dyslipidemia and insulin resistance, but also on damaging the liver itself and promoting what we call NASH, or nonalcoholic steatohepatitis,” said Kenneth Cusi, MD, FACP, FACE, who will open the session by examining the impact of hepatic triglycerides on metabolism and liver disease in obesity and diabetes.
Dr. Cusi, Chief of the Division of Endocrinology, Diabetes, and Metabolism at the University of Florida, noted that the increased risk of hepatocellular carcinoma and cardiovascular disease for patients with diabetes has been observed for decades, but researchers are just now showing that hepatic fat is a driver of these metabolic abnormalities.
“Understanding the mechanisms and clinical implications, particularly now that there are some pharmacologic treatments that reverse it, is of paramount importance to the medical community,” he said.
Dr. Cusi will review his team’s recently published research that illustrates how reversing the metabolic abnormalities that happen primarily in the functional adipose tissue has profound implications on the damage that liver fat imparts on the liver.
“Treatment with a drug that is available for the management of type 2 diabetes called pioglitazone showed that it can reverse the liver damage in about two-thirds of the patients,” said Dr. Cusi, adding that this low-cost, generic medication may be for NASH what metformin is for the management of type 2 diabetes.
Dr. Cusi will also review a number of drugs currently under development that target metabolic abnormalities observed in NASH.
Alan R. Saltiel, PhD, Professor of Medicine and Pharmacology and Director of the Institute for Diabetes and Metabolic Health at the University of California, San Diego, will take an in-depth look at the cross talk between fat cells and the liver, and between fat cells and themselves during his lecture “Liver and Subcutaneous Adipose Tissue Cross Talk.”
“There’s one signal that we are particularly interested in, the hormone called interleukin 6 [IL-6], or more particularly, the cues that tell the fat cells to release IL-6 and what IL-6 is doing to the liver to tell it whether to reduce its output of glucose,” he said.
Dr. Saltiel’s research team just completed a clinical trial, not yet published, of a drug discovered in his lab that had a positive impact on diabetes and fatty liver. He will share some of the team’s findings during his talk.
“The drug we are studying actually sensitizes fat cells to adrenaline, which comes from the nerves that originate from the brain in the vicinity of the fat cell,” he explained. “One of the things adrenaline does is tell the cells to secrete IL-6. IL-6 talks to liver and other fat cells to burn fat and tells the liver to stop producing glucose in the fasting state. This is not the whole story, but it’s part of the story of how the drug works.”
Dr. Saltiel said this ongoing research provides a glimpse into the complex network of pathways that regulate energy balance and glucose metabolism, and opens the door to understanding how fat cells talk to each other and through the liver via IL-6.
“It’s probably not the only hormone, but it suggests that it’s one example of what’s probably a symphony of hormones in use to orchestrate the control of metabolism,” he said. “What’s really interesting is we are learning that there are a lot of ways in which cells control energy balance, especially energy expenditure. This is important in obesity and diabetes.”
Another evolving research area involves the contribution of the gut microbiota to chronic liver disease, in particular nonalcoholic fatty liver disease (NAFLD), NASH, and alcoholic liver disease.
Bernd Schnabl, MD, Associate Professor in Gastroenterology at the University of California, San Diego, will review the latest research in the cross talk between the gut and the liver.
“We have known for a very long time that liver disease is a dysbiosis-driven disease,” said Dr. Schnabl, noting that the links between the gut microbiome and the liver have been known for many years. “The logical evidence for this is because all of the venous blood from the intestine is directly drained into portal vein circulation. The portal vein connects the intestine with the liver. So we not only get all nutrients from the intestine delivered to the liver, but everything else that’s coming from the intestine, in particular bacterial or fungal toxins.”
Dr. Schnabl will highlight the changes that occur in the gut microbiome during nonalcoholic and alcoholic liver disease, and how these changes contribute to disease, including the role of metabolites and bile acids in the onset of NAFLD, NASH, and alcoholic liver disease. He will also discuss therapeutic interventions that can modulate the intestinal homeostasis, and how to manipulate the microbiome to benefit the liver.
“We can use prebiotics, probiotics, and more targeted approaches,” he said. “We can target either a metabolite in the intestinal lumen or we can target a host gene that’s affected by these microbiome changes and specifically reach to this target with the aim of restoring the intestinal homeostasis, with the ultimate aim of ameliorating liver disease.”
The U.S. Food and Drug Administration has not approved any drugs to manipulate the gut microbiome for the treatment of liver disease, but precision microbiome approaches are in a preclinical state, Dr. Schnabl said.
Also during the symposium, Hannele Yki-Järvinen MD, FRCP, Professor of Medicine at the University of Helsinki, Finland, will compare the metabolic impact of acquired and genetic fatty liver disease.