Chen Xue, Wang Long, Denning Krista L, Mazur Anna, Xu Yujuan, Wang Kesheng, Lawrence Logan M, Wang Xiaodong, Lu Yongke
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV 25755, USA.
Department of Pathology, Guiqian International General Hospital, 1 Dongfeng Ave., Wudang, Guiyang 550018, China.
Biomedicines. 2024 Apr 30;12(5):988. doi: 10.3390/biomedicines12050988.
Obesity results in hepatic fat accumulation, i.e., steatosis. In addition to fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in the mitochondria and peroxisomes. Usually, very long-chain and branched-chain fatty acids are the first to be oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in the mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout () mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high-fat diet (HFD) feeding, body weights were increased in PEX16 floxed () mice and adipose-specific PEX16 knockout () mice, but not in the mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. HFD increased liver mass in the mice but somehow reduced the already enlarged liver mass in the mice. The basal levels of serum triglyceride, free fatty acids, and cholesterol were decreased, whereas serum bile acids were increased in the mice, and HFD-induced steatosis was not observed in the mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.
肥胖会导致肝脏脂肪蓄积，即脂肪变性。除了脂肪超载外，脂肪酸β氧化受损也会促进脂肪变性。脂肪酸β氧化发生在线粒体和过氧化物酶体中。通常，极长链和支链脂肪酸首先在过氧化物酶体中被氧化，生成的短链脂肪酸再在线粒体中进一步氧化。过氧化物酶体生物发生受过氧化物酶16（PEX16）调控。在肝脏特异性PEX16基因敲除（）小鼠中，肝细胞过氧化物酶体缺失，但肝细胞增殖，肝脏质量增大。这些结果表明，正常肝脏过氧化物酶体可抑制肝细胞增殖和肝脏大小。高脂饮食（HFD）喂养后，PEX16条件性敲除（）小鼠和脂肪特异性PEX16基因敲除（）小鼠体重增加，但基因敲除小鼠体重未增加，这表明肥胖的发生受肝脏PEX16调控，而非脂肪组织中的PEX16。HFD使基因敲除小鼠肝脏质量增加，但却使基因敲除小鼠本已增大的肝脏质量有所减小。基因敲除小鼠血清甘油三酯、游离脂肪酸和胆固醇的基础水平降低，而血清胆汁酸水平升高，且基因敲除小鼠未出现HFD诱导的脂肪变性。这些结果表明，正常肝脏过氧化物酶体有助于肝脏脂肪变性和肥胖症的发生发展。
