Exogenous H2S switches cardiac energy substrate metabolism by regulating SIRT3 expression in db/db mice
Exogenous H2S switches cardiac energy substrate metabolism by regulating SIRT3 expression in db/db mice
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外源 H2S 通过调节 db/db 小鼠 SIRT3 表达来改变心脏能量底物代谢
DOI：
10.1007/s00109-017-1616-3
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发表时间：
2018-04-01
影响因子：
4.7
通讯作者：
Zhang, Weihua
中科院分区：
文献类型：
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作者：
Sun, Yu;Tian, Zhiliang;Zhang, Weihua
摘要硫化氢（H2S）具有多种生理功能，如抗高血压、抗增殖、调节ATP合成和活性氧的产生等。Sirtuin 3（SIRT 3）是一种调节线粒体能量代谢的NAD+依赖性脱乙酰酶。H2S在糖尿病心肌病（DCM）能量代谢中的作用可能与调节SIRT 3表达有关;然而，这种作用仍有待阐明。我们推测外源性H2S可能通过促进db/db小鼠心脏组织SIRT 3的表达，通过赖氨酸乙酰化改变心脏能量代谢底物偏好。Db/db小鼠、新生大鼠心肌细胞和H9 c2细胞系用高糖、油酸盐和棕榈酸盐处理，用作2型糖尿病的动物和细胞模型。使用LC-MS/MS，我们鉴定了76种增加乙酰化的蛋白质，包括与NaHS处理的db/db小鼠心脏中的脂肪酸β-氧化相关的8种酶和三羧酸（TCA）循环的7种酶。外源H2S恢复了NAMPT的表达，NAD+/NADH比值提高了SIRT 3的表达和活性。由于SIRT 3的活化，脂肪酸β-氧化酶LCAD的乙酰化水平和活性以及葡萄糖氧化酶PDH、IDH 2和CS的乙酰化降低，这导致PDH、IDH 2和CS的活化。我们的研究结果表明，H2S通过调节SIRT 3通路诱导DCM心肌能量底物利用从脂肪酸β-氧化转换为葡萄糖氧化，H2S调节db/DCM心肌组织中脂肪酸氧化和葡萄糖氧化的乙酰化水平和酶活性。外源性H2S通过上调SIRT 3的表达和活性降低线粒体乙酰化水平，H2S诱导心肌细胞乙酰化水平的转换，从脂肪酸氧化为葡萄糖的能量底物利用。
AbstractHydrogen sulfide (H2S) is involved in diverse physiological functions, such as anti-hypertension, anti-proliferation, regulating ATP synthesis, and reactive oxygen species production. Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase that regulates mitochondrial energy metabolism. The role of H2S in energy metabolism in diabetic cardiomyopathy (DCM) may be related to regulate SIRT3 expression; however, this role remains to be elucidated. We hypothesized that exogenous H2S could switch cardiac energy metabolic substrate preference by lysine acetylation through promoting the expression of SIRT3 in cardiac tissue of db/db mice. Db/db mice, neonatal rat cardiomyocytes, and H9c2 cell line with the treatment of high glucose, oleate, and palmitate were used as animal and cellular models of type 2 diabetes. Using LC-MS/MS, we identified 76 proteins that increased acetylation, including 8 enzymes related to fatty acid β-oxidation and 7 enzymes of the tricarboxylic acid (TCA) cycle in the db/db mice hearts compared to those with the treatment of NaHS. Exogenous H2S restored the expression of NAMPT and the ratio of NAD+/NADH enhanced the expression and activity of SIRT3. As a result of activation of SIRT3, the acetylation level and activity of fatty acid β-oxidation enzyme LCAD and the acetylation of glucose oxidation enzymes PDH, IDH2, and CS were reduced which resulted in activation of PDH, IDH2, and CS. Our finding suggested that H2S induced a switch in cardiac energy substrate utilization from fatty acid β-oxidation to glucose oxidation in DCM through regulating SIRT3 pathway.Key messagesH2S regulated the acetylation level and activities of enzymes in fatty acid oxidation and glucose oxidation in cardiac tissues of db/db mice.Exogenous H2S decreased mitochondrial acetylation level through upregulating the expression and activity of SIRT3 in vivo and in vitro.H2S induced a switch in cardiac energy substrate utilization from fatty acid oxidation to glucose.