RESUMEN
Very-low-density lipoprotein (VLDL), a triglyceride-rich lipoprotein secreted by hepatocytes, is pivotal for supplying peripheral tissues with fatty acids for energy production. As if walking on a tightrope, perturbations in the balance of VLDL metabolism contribute to cardiometabolic dysfunction, promoting pathologies such as cardiovascular disease (CVD) or metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the advent of lipid-lowering therapies, including statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, risks for cardiovascular events persist. With limitations to currently available CVD therapeutics and no US Food and Drug Administration (FDA)-approved treatment for MASLD, this review summarizes the current understanding of VLDL metabolism that sheds light on novel therapeutic avenues to pursue for cardiometabolic disorders.
RESUMEN
AIM: Endothelial lipase (EL) plays an important role in lipoprotein metabolism. Our recent study showed that increased hepatic expression of EL attenuates diet-induced hypercholesterolemia, thus subsequently reducing atherosclerosis in transgenic (Tg) rabbits. However, it is yet to be determined whether increased EL activity itself per se is anti-atherogenic or whether the anti-atherogenic effect of EL is exclusively dependent on its lipid-lowering effect. METHODS: To determine the mechanisms underlying EL-mediated anti-atherogenic effect, we fed Tg and non-Tg rabbits diets containing different amounts of cholesterol to make their plasma cholesterol levels similarly high. Sixteen weeks later, we examined their lipoprotein profiles and compared their susceptibility to atherosclerosis. RESULTS: With Tg and non-Tg rabbits having hypercholesterolemia, the plasma lipids and lipoprotein profiles were observed to be similar, while pathological examinations revealed that lesion areas of both aortic and coronary atherosclerosis of Tg rabbits were not significantly different from non-Tg rabbits. Moreover, Tg rabbits exhibited faster clearance of DiI-labeled ß-VLDLs than non-Tg rabbits. CONCLUSION: The results of our study suggest that the enhancement of ß-VLDL catabolism is the major mechanism for atheroprotective effects of EL in Tg rabbits.
Asunto(s)
Aterosclerosis , Endotelio Vascular/metabolismo , Hipercolesterolemia , Lipasa/metabolismo , Lipoproteínas IDL/metabolismo , Animales , Animales Modificados Genéticamente , Arterias/metabolismo , Arterias/patología , Aterosclerosis/sangre , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Hipercolesterolemia/sangre , Hipercolesterolemia/metabolismo , Metabolismo de los Lípidos/fisiología , Lipoproteínas/sangre , Hígado/metabolismo , Conejos , Triglicéridos/sangreRESUMEN
Liver X receptor (LXR) agonists exert potent antiatherosclerotic actions but simultaneously induce excessive triglyceride (TG) accumulation in the liver. To obtain a detailed insight into the underlying mechanism of hepatic TG accumulation, we used a novel computational modeling approach called analysis of dynamic adaptations in parameter trajectories (ADAPT). We revealed that both input and output fluxes to hepatic TG content are considerably induced on LXR activation and that in the early phase of LXR agonism, hepatic steatosis results from only a minor imbalance between the two. It is generally believed that LXR-induced hepatic steatosis results from increased de novo lipogenesis (DNL). In contrast, ADAPT predicted that the hepatic influx of free fatty acids is the major contributor to hepatic TG accumulation in the early phase of LXR activation. Qualitative validation of this prediction showed a 5-fold increase in the contribution of plasma palmitate to hepatic monounsaturated fatty acids on acute LXR activation, whereas DNL was not yet significantly increased. This study illustrates that complex effects of pharmacological intervention can be translated into distinct patterns of metabolic regulation through state-of-the-art mathematical modeling.