Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Pediatría, México City, Mexico.
Biofactors. 2012 Sep-Oct;38(5):387-94. doi: 10.1002/biof.1034. Epub 2012 Jul 17.
In addition to its role as a carboxylase cofactor, biotin modifies gene expression and has manifold effects on systemic processes. Several studies have shown that biotin supplementation reduces hypertriglyceridemia. We have previously reported that this effect is related to decreased expression of lipogenic genes. In the present work, we analyzed signaling pathways and posttranscriptional mechanisms involved in the hypotriglyceridemic effects of biotin. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg of free biotin/kg diet, respectively for 8 weeks after weaning. The abundance of mature sterol regulatory element-binding protein (SREBP-1c), fatty-acid synthase (FAS), total acetyl-CoA carboxylase-1 (ACC-1) and its phosphorylated form, and AMP-activated protein kinase (AMPK) were evaluated in the liver. We also determined the serum triglyceride concentrations and the hepatic levels of triglycerides and cyclic GMP (cGMP). Compared to the control group, biotin-supplemented mice had lower serum and hepatic triglyceride concentrations. Biotin supplementation increased the levels of cGMP and the phosphorylated forms of AMPK and ACC-1 and decreased the abundance of the mature form of SREBP-1c and FAS. These data provide evidence that the mechanisms by which biotin supplementation reduces lipogenesis involve increased cGMP content and AMPK activation. In turn, these changes lead to augmented ACC-1 phosphorylation and decreased expression of both the mature form of SREBP-1c and FAS. Our results demonstrate for the first time that AMPK is involved in the effects of biotin supplementation and offer new insights into the mechanisms of biotin-mediated hypotriglyceridemic effects.
除了作为羧化酶辅助因子的作用外，生物素还可修饰基因表达，并对全身过程产生多种影响。几项研究表明，生物素补充可降低高甘油三酯血症。我们之前曾报道过，这种作用与脂肪生成基因表达降低有关。在本工作中，我们分析了生物素降低甘油三酯作用所涉及的信号通路和转录后机制。雄性 BALB/cAnN Hsd 小鼠在断奶后 8 周内分别用对照或生物素补充饮食（分别为 1.76 或 97.7mg 游离生物素/kg 饮食）喂养。在肝脏中评估成熟固醇调节元件结合蛋白（SREBP-1c）、脂肪酸合酶（FAS）、总乙酰辅酶 A 羧化酶-1（ACC-1）及其磷酸化形式和 AMP 激活蛋白激酶（AMPK）的丰度。我们还测定了血清甘油三酯浓度以及肝组织甘油三酯和环鸟苷酸（cGMP）水平。与对照组相比，补充生物素的小鼠血清和肝组织甘油三酯浓度较低。生物素补充增加了 cGMP 水平以及 AMPK 和 ACC-1 的磷酸化形式，并降低了成熟形式的 SREBP-1c 和 FAS 的丰度。这些数据提供了证据，表明生物素补充降低脂肪生成的机制涉及 cGMP 含量增加和 AMPK 激活。反过来，这些变化导致 ACC-1 磷酸化增加和成熟形式的 SREBP-1c 和 FAS 表达降低。我们的结果首次证明 AMPK 参与了生物素补充的作用，并为生物素介导的降低甘油三酯作用的机制提供了新的见解。
