Bassett Healthcare , Cooperstown, NY , USA ; Clore Laboratory, University of Buckingham , Buckingham , UK.
Clore Laboratory, University of Buckingham , Buckingham , UK.
PeerJ. 2014 Oct 7;2:e611. doi: 10.7717/peerj.611. eCollection 2014.
We determined the effect of butyrate and other short-chain fatty acids (SCFA) on rates of lipolysis in 3T3-L1 adipocytes. Prolonged treatment with butyrate (5 mM) increased the rate of lipolysis approximately 2-3-fold. Aminobutyric acid and acetate had little or no effect on lipolysis, however propionate stimulated lipolysis, suggesting that butyrate and propionate act through their shared activity as histone deacetylase (HDAC) inhibitors. Consistent with this, the HDAC inhibitor trichostatin A (1 µM) also stimulated lipolysis to a similar extent as did butyrate. Western blot data suggested that neither mitogen-activated protein kinase (MAPK) activation nor perilipin down-regulation are necessary for SCFA-induced lipolysis. Stimulation of lipolysis with butyrate and trichostatin A was glucose-dependent. Changes in AMP-activated protein kinase (AMPK) phosphorylation mediated by glucose were independent of changes in rates of lipolysis. The glycolytic inhibitor iodoacetate prevented both butyrate- and tumor necrosis factor-alpha-(TNF-α) mediated increases in rates of lipolysis indicating glucose metabolism is required. However, unlike TNF-α- , butyrate-stimulated lipolysis was not associated with increased lactate release or inhibited by activation of pyruvate dehydrogenase (PDH) with dichloroacetate. These data demonstrate an important relationship between lipolytic activity and reported HDAC inhibitory activity of butyrate, other short-chain fatty acids and trichostatin A. Given that HDAC inhibitors are presently being evaluated for the treatment of diabetes and other disorders, more work will be essential to determine if these effects on lipolysis are due to inhibition of HDAC.
我们测定了丁酸盐和其他短链脂肪酸 (SCFA) 对 3T3-L1 脂肪细胞脂肪分解率的影响。丁酸盐（5mM）的长期处理将脂肪分解率提高了约 2-3 倍。氨基丁酸和乙酸盐对脂肪分解几乎没有影响，但丙酸盐刺激了脂肪分解，这表明丁酸盐和丙酸盐通过作为组蛋白去乙酰化酶 (HDAC) 抑制剂的共同活性发挥作用。与此一致，HDAC 抑制剂曲古抑菌素 A（1µM）也刺激脂肪分解的程度与丁酸盐相似。Western blot 数据表明，SCFA 诱导的脂肪分解既不需要丝裂原活化蛋白激酶 (MAPK) 激活，也不需要脂联素下调。丁酸盐和曲古抑菌素 A 刺激脂肪分解是葡萄糖依赖性的。葡萄糖介导的 AMP 激活蛋白激酶 (AMPK) 磷酸化的变化与脂肪分解率的变化无关。糖酵解抑制剂碘乙酸盐可防止丁酸盐和肿瘤坏死因子-α（TNF-α）介导的脂肪分解率增加，表明需要葡萄糖代谢。然而，与 TNF-α 不同，丁酸盐刺激的脂肪分解与乳酸释放增加无关，也不受二氯乙酸激活丙酮酸脱氢酶 (PDH) 的抑制。这些数据表明脂肪分解活性与丁酸盐、其他短链脂肪酸和曲古抑菌素 A 的报道的 HDAC 抑制活性之间存在重要关系。鉴于 HDAC 抑制剂目前正在评估用于治疗糖尿病和其他疾病，需要进行更多的工作来确定这些对脂肪分解的影响是否归因于 HDAC 的抑制。
