Yeh Yu-Sheng, Jheng Huei-Fen, Iwase Mari, Kim Minji, Mohri Shinsuke, Kwon Jungin, Kawarasaki Satoko, Li Yongjia, Takahashi Haruya, Ara Takeshi, Nomura Wataru, Kawada Teruo, Goto Tsuyoshi
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan.
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan; Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
iScience. 2018 Nov 30;9:175-191. doi: 10.1016/j.isci.2018.10.019. Epub 2018 Oct 21.
The mevalonate pathway is essential for the synthesis of isoprenoids and cholesterol. Adipose tissue is known as a major site for cholesterol storage; however, the role of the local mevalonate pathway and its synthesized isoprenoids remains unclear. In this study, adipose-specific mevalonate pathway-disrupted (aKO) mice were generated through knockout of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR). aKO mice showed serious lipodystrophy accompanied with glucose and lipid metabolic disorders and hepatomegaly. These metabolic variations in aKO mice were dramatically reversed after fat transplantation. In addition, HMGCR-disrupted adipocytes exhibited loss of lipid accumulation and an increase of cell death, which were ameliorated by the supplementation of mevalonate and geranylgeranyl pyrophosphate but not farnesyl pyrophosphate and squalene. Finally, we found that apoptosis may be involved in adipocyte death induced by HMGCR down-regulation. Our findings indicate that the mevalonate pathway is essential for adipocytes and further suggest that this pathway is an important regulator of adipocyte turnover.
甲羟戊酸途径对于类异戊二烯和胆固醇的合成至关重要。脂肪组织是胆固醇储存的主要部位；然而，局部甲羟戊酸途径及其合成的类异戊二烯的作用仍不清楚。在本研究中，通过敲除3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（HMGCR）产生了脂肪特异性甲羟戊酸途径破坏（aKO）小鼠。aKO小鼠表现出严重的脂肪营养不良，并伴有葡萄糖和脂质代谢紊乱以及肝肿大。脂肪移植后，aKO小鼠的这些代谢变化得到了显著逆转。此外，HMGCR破坏的脂肪细胞表现出脂质积累减少和细胞死亡增加，补充甲羟戊酸和香叶基香叶基焦磷酸可改善这些情况，但补充法尼基焦磷酸和角鲨烯则无效。最后，我们发现细胞凋亡可能参与了由HMGCR下调诱导的脂肪细胞死亡。我们的研究结果表明甲羟戊酸途径对脂肪细胞至关重要，并进一步表明该途径是脂肪细胞更新的重要调节因子。
