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Publications of the Week

The Role of Bone Morphogenetic Protein Signaling in Non-Alcoholic Fatty Liver Disease

By July 2, 2020No Comments

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This week we profile a recent publication in Scientific Reports from the laboratory
of Dr. Rajeev Malhotra (pictured) at Massachusetts General Hospital.

Can you provide a brief overview of your lab’s current research focus?

Atherosclerosis and its downstream clinical consequences, including myocardial infarction (MI), stroke, and peripheral vascular disease, affect more than 40 million people in the United States and is the number one cause of morbidity and mortality worldwide. Atherosclerotic plaques build up on the walls of blood vessels and consist of lipids and calcium deposits. Although treatments exist that target risk factors for cardiovascular disease (such as dyslipidemia or anti-hypertensive agents), there is currently no treatment to directly prevent or reverse vascular calcification. Our laboratory studies the molecular mechanisms by which atherosclerosis and calcification develop in the vessel wall in the hopes of uncovering novel targets for the development of new disease treatments.

Our research program focuses on the role of multiple signaling pathways in the pathogenesis of atherosclerosis, vascular calcification, and cardiometabolic disorders such as non-alcoholic fatty liver disease. We have identified polymorphisms in the HDAC9 locus that confer increased risk of atherocalcific disease, MI, and stroke in humans and have demonstrated that HDAC9 promotes vascular calcification using both in vitro and in vivo models. Furthermore, our work has demonstrated that pharmacologic inhibition of bone morphogenetic protein (BMP) signaling reduces the burden of vascular calcification, likely through inhibition of endothelial-to-mesenchymal transition. More recently, our laboratory has identified an essential role for BMP signaling in non-alcoholic fatty liver disease. Using a combination of human genetic and biomarker approaches, as well as in vitro and in vivo models, we aim to identify novel genetic and molecular mechanisms of cardiovascular disease.

What is the significance of the findings in this publication?

The prevalence of non-alcoholic fatty liver disease (NAFLD) in adults exceeds 30% in Western countries and NAFLD portends increased risk of cardiovascular disease and mortality. Despite the growing burden and high morbidity and mortality associated with NAFLD, treatments are limited to risk factor modification including lifestyle intervention and management of co-morbid metabolic disease. This study identified a novel role of bone morphogenetic protein (BMP) signaling in NAFLD. Using a murine model of NAFLD, BMP signaling was found to be essential for the development of hepatic steatosis, independent of plasma cholesterol levels or glucose tolerance. In vitro, hepatocyte lipid accumulation and activity of an enzyme critical for triglyceride synthesis (DGAT2) were induced by BMP signaling. Based on these findings, we performed a candidate gene analysis that identified a rare variant of ALK6 (a BMP receptor) associated with NAFLD in a human cohort. Functional studies of this ALK6 variant revealed that it codes for a previously unknown constitutively active form of the BMP receptor. The important role of BMP signaling in the pathogenesis of NAFLD suggest that the BMP signal transduction pathway may be a successful target of future approaches to the treatment of this disease.

What are the next steps for this research?

Our future studies will focus on determining the specific mechanisms by which BMP signaling promotes triglyceride synthesis and accumulation in NAFLD. We will investigate the propensity of developing NAFLD in a novel murine model possessing the constitutively active ALK6 variant that we found to be associated with higher risk of NAFLD in humans. These experiments are aimed at improving our understanding of the molecular mechanisms of NAFLD. Furthermore, small molecule inhibitors of the BMP signaling pathway will be tested in additional models of NAFLD to determine their potential for utilization as a treatment of this frequent and highly comorbid condition.

This work was funded by:

We are grateful to the National Heart, Lung, and Blood Institute, American Heart Association, Sarnoff Cardiovascular Research Foundation, Hassenfeld Foundation, and Wild Family Foundation for supporting this work.

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