Research News

Published in eLife, a team led by Cleveland Clinic researchers have identified how a specific gene promotes non-alcoholic fatty liver disease (NAFLD), an increasingly prevalent condition that affects roughly one-third of American adults and is linked to obesity. Understanding the molecular pathways that contribute to the disease is critical in the search for new therapies.

Genome-wide association studies previously revealed that a common genetic variant linked to increased risk for a host of liver diseases, including NAFLD, is located near the genes MBOAT7 (membrane bound O-acyltransferase domain-containing 7) and TMC4 (transmembrane channel-like 4). Many researchers have suspected that downregulation or loss of function of one or both of these nearby genes may be a causative factor.

In this study, the research team—led by J. Mark Brown, PhD, Associate Staff, Department of Cardiovascular & Metabolic Sciences—was the first to study how silencing MBOAT7 and TMC4 affect NAFLD progression in a preclinical model. Using complimentary pharmacological and genetic approaches, they showed that “turning off” MBOAT7 alone was enough to drive NAFLD in models fed a high-fat diet. Loss of TMC4 did not have the same causative effect.

While in their studies the researchers harnessed the power of gene editing technology to suppress MBOAT7, they found that obesity may actually have the same effect. MBOAT7 expression patterns were compared between biopsied liver tissue taken from obese bariatric patients and normal weight controls. Their analyses revealed that MBOAT7 expression was significantly reduced in the obese population, offering a potential connection between weight, MBOAT7 suppression and NAFLD risk.

To understand how and why MBOAT7 expression affects NAFLD pathology and progression, however, Dr. Brown says it is important to consider MBOAT7’s enzymatic properties.

“We knew that the MBOAT7 gene codes for a specific enzyme. When we silenced MBOAT7, we saw, as expected, that levels of this enzyme fell significantly. As a result, there was an accumulation of its substrate, a molecule called LPI (lysophosphatidylinositol),” said Dr. Brown, who also directs research at the Cleveland Clinic Center for Microbiome and Human Health.

“To understand how higher than normal levels of LPI might affect disease, we administered it in vivo. We observed cellular changes indicative of increased liver inflammation and fibrosis, which are markers of NAFLD. What’s more, these pro-disease changes were dependent upon MBOAT7 expression.”

While additional research will be important, this study provides a clearer picture of the interplay between genetics, obesity and the risk for and severity of NAFLD. The team’s mechanistic investigations into MBOAT7 expression and substrate levels also offer promise for targeting LPI as a new and currently unexplored NAFLD treatment approach. With rates of obesity higher than ever before and steadily climbing, novel treatments for obesity-related conditions could have significant impact on not just human health, but also costs to public health and society.

Robert Helsley, PhD, Department of Internal Medicine, University of Cincinnati (formerly a member of the Brown laboratory) is first author on the study, which was funded in part by the American Heart Association and the National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute on Alcohol Abuse and Alcoholism (all parts of the National Institutes of Health).