Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sci Rep. 2020 Oct 27;10(1):18367. doi: 10.1038/s41598-020-75615-3.
Medium-chain triglycerides (MCT), containing C-C fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C/C fatty acids or coconut oil, which is rich in C, for five weeks. Coconut oil, but not C/C feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. C-C degradation was significantly reduced in Sirt5KO liver. This decrease was localized to the mitochondrial β-oxidation pathway, as Sirt5KO mice exhibited no change in peroxisomal C β-oxidation. Endoplasmic reticulum ω-oxidation, a minor fatty acid degradation pathway known to be stimulated by C accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C. These studies reveal a role for Sirt5 in regulating the hepatic response to MCT and may shed light into the pathogenesis of periportal steatosis, a hallmark of human pediatric non-alcoholic fatty liver disease.
中链甘油三酯（MCT）含有 C-C 脂肪酸，用于治疗多种儿科疾病，并被广泛用作营养补充剂。在这里，我们通过用含有 C/C 脂肪酸或富含 C 的椰子油的高脂肪饮食喂养 Sirt5 敲除小鼠（Sirt5KO）五周，研究了去乙酰化酶 Sirt5 在 MCT 代谢中的作用。椰子油而非 C/C 喂养会诱导 Sirt5KO 小鼠门脉周围大泡性脂肪变性。Sirt5KO 肝脏中的 C-C 降解明显减少。这种减少局限于线粒体 β-氧化途径，因为 Sirt5KO 小鼠的过氧化物酶体 C β-氧化没有变化。内质网 ω-氧化是一种已知被 C 积累刺激的次要脂肪酸降解途径，在 Sirt5KO 肝脏中增加。当喂食椰子油时，缺乏另一种线粒体 C 氧化酶长链酰基辅酶 A 脱氢酶（LCAD）的小鼠也会发生门脉周围大泡性脂肪变性，这证实了线粒体 C 氧化缺陷足以诱导脂肪变性表型。Sirt5KO 肝脏表现出正常的 LCAD 活性，但在 C 存在下线粒体酰基辅酶 A 合成酶活性降低。这些研究揭示了 Sirt5 在调节肝脏对 MCT 的反应中的作用，并可能为门脉周围脂肪变性的发病机制提供线索，门脉周围脂肪变性是人类儿科非酒精性脂肪性肝病的一个标志。
