Abstract Body: Atherosclerotic coronary artery disease (CAD) is the main contributor to the global cardiovascular disease health crisis and has been exacerbated by the spread of obesity and diabetes. Although tremendous progress in treatments have been made, the continual rise of CAD necessitates a more sophisticated understanding of the pathophysiological mechanisms contributing to disease. Using an integrative genomic screening strategy in human hepatic cells, we previously identified an unexpected role for the mitochondrial enzyme, metabolism of cobalamin associated B (MMAB), in regulating cholesterol homeostasis through the modulation of propionate byproducts. More recently, MMAB was identified as a key driver gene of a liver-specific regulatory co-expression network that associates with several metabolic traits in humans including BMI, plasma lipid levels and HbA1c. However, the mechanisms linking MMAB to cardiometabolic risk factors and its causal role in CAD remain unknown. Here, we demonstrate that MMAB is markedly upregulated in the livers and visceral adipose tissue of patients with CAD compared to case controls (adj P=4.0e-12 and 0.079, respectively). Similar increases in Mmab expression were observed in the liver and white adipose tissue of high-fat diet (HFD)-fed mice. In diet-induced murine models of obesity (HFD-fed C57BL6/J mice), whole-body inhibition of MMAB with antisense oligonucleotides (ASOs, 50 mg/kg x 6 weeks) led to significant reductions in fasting plasma triglyceride concentrations and improvements in glucose tolerance. Longer-term inhibition (12 weeks) was also associated with marked reductions in body weight and fat mass. Similar results were observed in Western-diet-fed Ldlr^-/- mice, suggesting a nutrient and LDLR-independent mechanism by which MMAB regulates triglyceride metabolism and adiposity. In atherosclerosis intervention studies with Western-diet fed Ldlr^-/- mice, whole-body MMAB inhibition significantly reduced aortic root lesion size and necrotic core area compared to controls. Mechanistically, MMAB ASO-mediated reductions in atheroprogression were associated with accelerated clearance of triglyceride-rich lipoproteins and reductions in circulating VLDL-triglyceride and VLDL/LDL-cholesterol levels. Collectively, these studies identify an LDLR-independent mechanism by which MMAB regulates obesity and atheroprogression and warrant further investigations into the tissue-specific roles of MMAB in regulating cardiometabolic risk.