Christie A W, McCormick D K, Emmison N, Kraemer F B, Alberti K G, Yeaman S J
Department of Biochemistry and Genetics, University of Newcastle upon Tyne, UK.
Diabetologia. 1996 Jan;39(1):45-53. doi: 10.1007/BF00400412.
Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 mumol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p < 0.05) decreased by 100 mumol/l acipimox, whereas, in the absence of adenosine deaminase, 100 mumol/l acipimox showed no significant (p > 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p < 0.05) reductions occurring at and above, 0.5 mumol/l and 10 mumol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p < 0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p < 0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes.
阿西莫司常用于治疗非胰岛素依赖型糖尿病患者的高甘油三酯血症，但其确切作用机制尚未阐明。我们研究了阿西莫司对从Wistar大鼠分离的附睾脂肪细胞中脂解调节级联反应的体外作用。阿西莫司以浓度依赖的方式抑制腺苷脱氨酶（1 U/ml）刺激的脂解速率，在阿西莫司浓度为10 μmol/l时达到接近基础值。异丙肾上腺素亚最大水平与腺苷脱氨酶（20 mU/ml）联合激活的脂解作用在100 μmol/l阿西莫司作用下显著（p<0.05）降低，而在无腺苷脱氨酶时，100 μmol/l阿西莫司无显著（p>0.05）抑制作用。这些发现表明，由腺苷调节的抗脂解机制也可能受阿西莫司调节。在存在腺苷脱氨酶（20 mU/ml）的情况下，阿西莫司以浓度依赖的方式降低了25 nmol/l异丙肾上腺素产生的细胞内环磷酸腺苷水平。在相同刺激水平下，阿西莫司在相同浓度范围内抑制环磷酸腺苷依赖性蛋白激酶活性比和脂解速率，分别在阿西莫司浓度为0.5 μmol/l及以上和10 μmol/l及以上时出现显著（p<0.05）降低。蛋白质印迹法显示，在脂解刺激（1 U/ml腺苷脱氨酶；100 nmol/l异丙肾上腺素）下，脂解速率增加三倍伴随着与脂质部分相关的激素敏感性脂肪酶显著（p<0.05）升高。阿西莫司（1 mmol/l）和胰岛素（1 nmol/l）将激素敏感性脂肪酶重新分布回胞质溶胶，同时脂肪细胞匀浆的脂肪饼部分相应显著（p<0.05）减少。总之，阿西莫司的抗脂解作用是通过抑制细胞内环磷酸腺苷水平介导的，随后环磷酸腺苷依赖性蛋白激酶活性降低，导致激素敏感性脂肪酶与脂肪细胞脂滴中三酰甘油底物的结合减少。
