Naringenin enhances the regression of atherosclerosis induced by a chow diet in Ldlr-/- mice

Background and aims: Naringenin is a citrus-derived flavonoid with lipid-lowering and insulin-sensitizing effects leading to athero-protection in Ldlr(-/-) mice fed a high-fat diet. However, the ability of naringenin to promote atherosclerosis regression is unknown. In the present study, we assessed the capacity of naringenin to enhance regression in Ldlr(-/-) mice with diet-induced intermediate atherosclerosis intervened with a chow diet. Methods: Male Ldlr(-/-) mice were fed a high-fat, cholesterol-containing (HFHC) diet for 12 weeks to induce intermediate atherosclerosis and metabolic dysfunction. Subsequently, a group of these mice were sacrificed for baseline analyses and the remainder either 1) continued on the HFHC diet, 2) switched to a chow diet or 3) switched to chow diet supplemented with naringenin. Results: After 12 weeks induction, intermediate lesions developed in the aortic sinus. Intervention with chow alone slowed lesion growth, while intervention with naringenin-supplemented chow completely halted lesion growth. Lesions were characterized by features of improved morphology. Compared to chow alone, naringenin reduced plaque macrophages and modestly increased smooth muscle cells. Investigating processes that contributed to improved plaque morphology, we showed naringenin further reduced plasma triglycerides and cholesterol compared to chow alone. Furthermore, elevated monocytosis and myelopoiesis were further corrected by intervention with naringenin compared to chow alone. Metabolically, naringenin enhanced the correction of insulin resistance, hepatic steatosis and obesity compared to chow alone, potentially contributing to enhanced regression. Conclusions: Naringenin supplementation to chow enhances atherosclerosis regression in male Ldlr(-/-) mice. These studies further underscore the potential therapeutic utility of naringenin.