A review of the studies on food-derived factors which regulate energy metabolism via the modulation of lipid-sensing nuclear receptors.

Obesity is one of the most important risk factors for chronic metabolic disorders. Molecular mechanisms underlying obesity-related metabolic disorders have not been completely elucidated. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and are key metabolic regulators of the whole-body energy metabolism. Certain enzymes involved in carbohydrate and lipid metabolism are directly regulated by PPARs via their interaction with specific response elements in their gene promoters. Many food factors act as ligands of PPARs and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors, leading to the attenuation of obesity-related metabolic disorders. In this review, we describe our current knowledge of the role of PPARs in the regulation of whole-body energy metabolism and several examples of food factors that act as ligands of PPARs, which may be useful in the management of obesity and the accompanying energy metabolism abnormalities. Abbreviations: WAT: white adipose tissue; PPAR: Peroxisome proliferators-activated receptor; RXR: retinoid X receptors; mTORC1: mechanistic target of rapamycin complex 1; PPRE: PPAR-responsive regulatory elements; NAFLD: nonalcoholic fatty liver disease; LPL: lipoprotein lipase; FGF21: fibroblast growth factor 21; BAT: brown adipose tissue; UCP1: uncoupling protein 1; LPC(16:0): 1-palmitoyl lysophosphatidylcholine; C/EBP: CCAAT-enhancer binding proteins; STAT5A: signal transduction and activator of transcription 5A; APO apolipoptotein; CBP: cAMP response element-binding protein-binding protein; PGC1A: PPARγ coactivator protein 1a; HFD: high-fat diet; TG: triglyceride; VLDL: very low density lipoprotein; HDL: high density lipoprotein.

Tratamiento de la hipertrigliceridemia: fibratos frente a ácidos grasos omega-3 / Treatment of hypertriglyceridemia: fibrates versus omega-3 fatty acids

Por ser un componente del síndrome metabólico y de la diabetes, entidades que en la actualidad son epidémicas, la hipertrigliceridemia (HTG) asociada con valores bajos de colesterol unido a lipoproteínas de alta densidad (cHDL) es la dislipidemia de presentación clínica más frecuente. Además, es la alteración lipídica característica de pacientes con enfermedad cardiaca coronaria. La HTG se debe a un aumento de la síntesis hepática de las lipoproteínas de muy baja densidad (VLDL), en general por un exceso de grasa visceral, o a un defecto en el aclaramiento de VLDL por hipoactividad de la lipoproteinlipasa (LPL) de causa genética o adquirida, y con frecuencia hay un defecto doble. Además del cHDL bajo, la HTG se asocia con la formación de partículas LDL densas y pequeñas, que son muy aterogénicas. Esto justifica que la HTG sea un factor de riesgo cardiovascular independiente y deba tratarse con la misma intensidad que la hipercolesterolemia. Actualmente, se recomiendan como deseables unas cifras de triglicéridos (TG) <150 mg/dl. El tratamiento conservador de la HTG con dieta y normalización del peso es muy eficaz, pero difícil de realizar en la práctica. El tratamiento farmacológico convencional de la HTG son los fibratos, agentes que activan el factor de transcripción PPAR-α. Esto promueve la oxidación de ácidos grasos y estimula la actividad LPL, lo que reduce los TG, y aumenta la síntesis de apoproteínas de las HDL, lo que incrementa las cifras de cHDL. En promedio, los fibratos reducen los TG un 36% y aumentan el cHDL un 8%. En dosis de 2-4 g/día, los ácidos grasos n-3 (AGn-3) de origen marino son tan eficaces como los fibratos en la reducción de TG y carecen de efectos secundarios. Los AGn-3 también son ligandos de PPAR-α, pero reducen la síntesis de ácidos grasos por mecanismos independientes, lo cual justifica que su efecto de reducción de los TG sea complementario del de los fibratos. La eficacia de los AGn-3 en la reducción de TG se ha demostrado en monoterapia y en tratamiento combinado con estatinas. En la HTG grave del síndrome de quilomicronemia, los AGn-3 añaden su efecto al de los fibratos, con lo que se consiguen reducciones adicionales de los TG de hasta un 50% y se minimiza el riesgo de pancreatitis. Por tanto, los fibratos y los AGn-3 no están enfrentados, sino que son complementarios (AU)

Hypertriglyceridemia (HTG) combined with a low highdensity lipoprotein (HDL) cholesterol level is the characteristic lipid abnormality in two prevalent conditions: the metabolic syndrome and diabetes. Moreover, it is also the commonest dyslipidemia in patients with coronary heart disease. HTG is caused by increased hepatic synthesis of very-low-density lipoprotein (VLDL), usually due to excess visceral fat, or to defective VLDL clearance secondary to genetic or acquired impairment of lipoprotein lipase activity (LPL). Frequently, there is both excess VLDL input to the circulation and reduced clearance. In addition to a low HDL cholesterol level, HTG is also associated with the formation of small dense low-density lipoprotein (LDL) particles that are particularly atherogenic. This explains why HTG is an independent cardiovascular risk factor that must be treated as intensively as hypercholesterolemia. At present, a triglyceride concentration < 150 mg/dL is regarded as desirable. Conservative treatment of HTG by lifestyle modification involving diet and weight loss is very effective but difficult to implement. Fibrates are the conventional pharmacological treatment for HTG. These agents are activators of transcription factor PPAR-α, and consequently promote fatty acid oxidation and enhance LPL. This, in turn, reduces the serum level and stimulates synthesis of HDL apolipoproteins, thereby increasing the HDL cholesterol level. On average, fibrates reduce the level by 36% and increase HDL cholesterol by 8%. Given at a dose of 2-4 g/day, marine omega-3 fatty acids are as effective as fibrates in lowering the triglyceride level. Moreover, they are devoid of side effects. In addition, omega-3 fatty acids also interact with PPAR-α, although they decrease fatty acid synthesis by alternative mechanisms. This explains why the lowering effect of omega-3 fatty acids is complementary to that of fibrates. Omega-3 fatty acids have been found to be effective in lowering the, triglyceride level when given either as monotherapy or in combination with statins. In the severe HTG found with chylomicronemia syndromes, the effect of omega-3 fatty acids is additive to that of fibrates, resulting in an additional reduction in levels of up to 50% beyond that induced by fibrates alone, thereby minimizing the risk of acute pancreatitis. Consequently, fibrates and omega-3 fatty acids do not have opposing actions. Instead, they complement each other when used for the treatment of hypertriglyceridemia (AU)