Obesity-associated chronic
inflammation contributes to metabolic dysfunction and propagates
atherosclerosis. Recent evidence suggests that increased
dietary cholesterol exacerbates
inflammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus
flavonoid naringenin to prevent these
cholesterol-induced perturbations is unknown. To assess the ability of
naringenin to prevent the amplified inflammatory response and
atherosclerosis induced by
dietary cholesterol, male Ldlr⁻/⁻ mice were fed either a
cholesterol-enriched high-fat or
low-fat diet supplemented with 3%
naringenin for 12 weeks.
Naringenin, through induction of hepatic
fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and
hyperlipidemia induced by both
cholesterol-rich diets.
Naringenin attenuated hepatic macrophage infiltration and
inflammation stimulated by
dietary cholesterol.
Insulin resistance, adipose tissue expansion, and
inflammation were alleviated by
naringenin.
Naringenin attenuated the
cholesterol-induced formation of both foam cells and expression of inflammatory markers in peritoneal macrophages.
Naringenin significantly decreased
atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic
lipids and a reversal of aortic
inflammation. We demonstrate that in mice fed
cholesterol-enriched diets,
naringenin attenuates peripheral and systemic
inflammation, leading to protection from
atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of
cholesterol-induced metabolic dysregulation.