Department of Pharmacology, Chongqing Medical University, Chongqing, China and Research Center of Neuroscience, Chongqing Medical University, Chongqing, China.
Department of Pharmacology, Chongqing Medical University, Chongqing, China.
Front Biosci (Landmark Ed). 2016 Jun 1;21(5):1052-60. doi: 10.2741/4440.
Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.
虽然小檗碱具有与核蛋白高亲和力的降血脂作用，但这种作用的潜在分子机制尚不清楚。在这里，我们确定小檗碱是否是过氧化物酶体增殖物激活受体α（PPARα）的激动剂，具有降低血脂的作用。基于细胞的报告基因分析表明，小檗碱选择性地激活 PPARα（EC50=0.58mM，Emax=102.4）。放射性配体结合试验表明，小檗碱直接与 PPARα的配体结合域结合（Ki=0.73mM），与非诺贝特的亲和力相似。HepG2 细胞和高脂血症大鼠肝组织中的 CPT-Iα 基因的 mRNA 和蛋白水平被小檗碱显著上调，这种作用可以被 MK886 阻断，MK886 是 PPARα 的非竞争性拮抗剂。用小檗碱和非诺贝特治疗高脂血症大鼠三个月的比较试验表明，这两种药物产生相似的降血脂作用，但小檗碱比非诺贝特更有效地增加高密度脂蛋白胆固醇。这些发现首次提供了小檗碱是 PPARα 的有效激动剂的证据，并且在治疗高脂血症方面似乎优于非诺贝特。
