Anders Naar

Anders Näär

Professor of Metabolic Biology and Vice Chair
Dept of Nutritional Sciences & Toxicology
Research Expertise and Interest
gene expression, microRNAs, Mammalian Cell Metabolism, Metabolic Diseases, obesity, Type 2 diabetes, NAFLD/NASH, cancer therapies
Research Description

The primary focus of my lab is to elucidate transcriptional and microRNA regulatory mechanisms governing cholesterol/lipid and metabolic homeostasis. Our studies over the last 20 years of the sterol- regulatory element-binding protein (SREBP) family of transcription factors, master regulators of cholesterol/lipid synthesis and trafficking, have led to an atomic-level understanding of the molecular mechanism of SREBP gene regulation. We have parlayed this detailed mechanistic knowledge to guide small molecule therapeutic targeting efforts resulting in the development of nanomolar inhibitors of the interaction of SREBPs with transcriptional co-activators. Ongoing NMR structure-guided medicinal chemistry efforts are aimed at further improving on these inhibitors, with the goal of identifying effective therapeutic modalities as treatments for diseases linked to abnormal cholesterol/lipids and metabolism, including many types of cancers, as well as metabolic syndrome, type 2 diabetes, cardiovascular disease. Our work is innovative as it challenges the prevalent dogma that protein-protein interactions are not druggable.

Our studies have also identified microRNAs as crucial regulators of cholesterol/lipids and metabolism. We uncovered miR-33a/b as intronic microRNAs present in the SREBP genes that act in concert with the host genes to govern cholesterol/lipid homeostasis. Based on potent effects of antisense oligonucleotides (ASOs) targeting miR-33a/b on atherosclerosis in rodent models, we are currently pursuing state-of-the art locked nucleic acid (LNA) ASO technologies as novel and safe treatments for familial hypercholesterolemia and other cardiovascular diseases.

Employing genome-wide association study data from >188,000 individuals we have identified a microRNA, miR-128-1, as a crucial regulator of circulating cholesterol and triglycerides. Surprisingly, miR-128- 1 is located in a genomic region on human chromosome 2 that is also strongly linked to recent positive selection, type 2 diabetes, and obesity. Based on our supportive in vivo data in several mouse obesity and metabolic disease models, we hypothesize that miR-128-1 represents a thrifty microRNA that acts as a potent negative regulator of energy expenditure, selected as a human evolutionary adaptation to promote fat storage to survive famine in ancient times. Currently, this represents a maladaptation in the developed world with abundant food, resulting in increased risk for cardio-metabolic diseases such as coronary artery disease, Metabolic Syndrome (MetS), obesity, type 2 diabetes, and non-alcoholic fatty liver diseases (NAFLD/NASH). Indeed, our ongoing and planned studies are aimed at developing LNA ASO modalities targeting miR-128-1 for the treatment of these metabolic diseases, and unpublished results from mouse obesity and NASH models look very promising. We have also unexpectedly found a link of miR-128-1 to Duchenne Muscular Dystrophy (DMD), a rare and early lethal muscle wasting disorder, and we are investigating a potential pathological disease modifying role of miR-128-1 in DMD, and whether it might represent a target for LNA ASOs as a novel DMD treatment in conjunction with other approaches such as exon-skipping ASO modalities.

Altogether, we are taking advantage of deep insights into molecular underpinnings of common and rare human diseases gained from our mechanistic studies to develop novel therapeutic targeting strategies.

In the News

April 4, 2019

Insulin Insights

Many aspects of insulin signaling remain unclear, particularly its long-term effects on cells, and there are currently no effective cures for the hundreds of millions of people around the world living with diabetes. Now, Professor Anders Näär and collaborators from Harvard Medical School (HMS) have made key new insights into the molecular behavior of insulin.

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