Brass E P, Beyerinck R A
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Biochem J. 1988 Mar 15;250(3):819-25. doi: 10.1042/bj2500819.
Accumulation of propionate, or its metabolic product propionyl-CoA, can disrupt normal cellular metabolism. The present study examined the effects of propionate, or propionyl-CoA generated during the oxidation of odd-chain-length fatty acids, on hepatic oxidation of short- and medium-chain-length fatty acids. In isolated hepatocytes, ketone-body formation from odd-chain-length fatty acids was slow as compared with even-chain-length fatty acid substrates, and increased as the carbon chain length was increased from five to seven to nine. In contrast, rates of ketogenesis from butyrate, hexonoate and octanoate were all approximately equal. Propionate (10 mM) inhibited ketogenesis from butyrate, hexanoate and octanoate by 81%, 53% and 18% respectively. Addition of carnitine had no effect on ketogenesis from the even-chain-length fatty acids, but increased the rate of ketone-body formation from pentanoate (by 53%), heptanoate (by 28%) and from butyrate or hexanoate in the presence of propionate. The inhibitory effect of propionate could not be explained by shunting acetyl-CoA into the tricarboxylic acid cycle, as CO2 formation from butyrate was also decreased by propionate. Examination of the hepatocyte CoA pool during oxidation of butyrate demonstrated that addition of propionate decreased acetyl-CoA and CoA as propionyl-CoA accumulated. Addition of carnitine decreased propionyl-CoA by 50% (associated with production of propionylcarnitine) and increased acetyl-CoA and CoA. Similar changes in the CoA pool were seen during the oxidation of pentanoate. These results demonstrate that accumulation of propionyl-CoA results in inhibition of short-chain fatty acid oxidation. Carnitine can partially reverse this inhibition. Changes in the hepatocyte CoA pool are consistent with carnitine acting by generating propionylcarnitine, thereby decreasing propionyl-CoA and increasing availability of free CoA. The data provide further evidence of the potential cellular toxicity from organic acid accretion, and supports the concept that carnitine's interaction with the cellular CoA pool can have a beneficial effect on cellular metabolism and function under conditions of unusual organic acid accumulation.
丙酸或其代谢产物丙酰辅酶A的积累会扰乱正常的细胞代谢。本研究考察了丙酸或奇数链长脂肪酸氧化过程中生成的丙酰辅酶A对短链和中链脂肪酸肝脏氧化的影响。在分离的肝细胞中，与偶数链长脂肪酸底物相比，奇数链长脂肪酸生成酮体的速度较慢，且随着碳链长度从5增加到7再到9而加快。相比之下，丁酸、己酸和辛酸的生酮速率大致相同。丙酸（10 mM）分别抑制丁酸、己酸和辛酸生酮81%、53%和18%。添加肉碱对偶数链长脂肪酸的生酮没有影响，但增加了戊酸（增加53%）、庚酸（增加28%）以及在有丙酸存在时丁酸或己酸的酮体生成速率。丙酸的抑制作用不能通过将乙酰辅酶A分流到三羧酸循环来解释，因为丙酸也降低了丁酸生成二氧化碳的量。在丁酸氧化过程中检测肝细胞辅酶A库发现，随着丙酰辅酶A的积累，添加丙酸会降低乙酰辅酶A和辅酶A。添加肉碱使丙酰辅酶A减少50%（与生成丙酰肉碱有关），并增加了乙酰辅酶A和辅酶A。在戊酸氧化过程中也观察到辅酶A库有类似变化。这些结果表明，丙酰辅酶A的积累会抑制短链脂肪酸氧化。肉碱可以部分逆转这种抑制作用。肝细胞辅酶A库的变化与肉碱通过生成丙酰肉碱起作用一致，从而减少丙酰辅酶A并增加游离辅酶A的可用性。这些数据进一步证明了有机酸积累可能产生的细胞毒性，并支持这样的概念，即在异常有机酸积累的情况下，肉碱与细胞辅酶A库的相互作用可对细胞代谢和功能产生有益影响。
