Abstract：
Hepatic steatosis, the first step in the development of nonalcoholic fatty liver disease (NAFLD), is frequently observed in the aging population. However, the underlying molecular mechanism remains largely unknown. In this study, we first employed GSEA enrichment analysis to identify short-chain acyl-CoA dehydrogenase (SCAD), which participates in the mitochondrial β-oxidation of fatty acids and may be associated with hepatic steatosis in elderly individuals. Subsequently, we examined SCAD expression and hepatic triglyceride content in various aged humans and mice and found that triglycerides were markedly increased and that SCAD was upregulated in aged livers. Our further evidence in SCAD-ablated mice suggested that SCAD deletion was able to slow liver aging and ameliorate aging-associated fatty liver. Examination of the molecular pathways by which the deletion of SCAD attenuates steatosis revealed that the autophagic degradation of lipid droplets, which was not detected in elderly wild-type mice, was maintained in SCAD-deficient old mice. This was due to the decrease in the production of acetyl-coenzyme A (acetyl-CoA), which is abundant in the livers of old wild-type mice. In conclusion, our findings demonstrate that the suppression of SCAD may prevent age-associated hepatic steatosis by promoting lipophagy and that SCAD could be a promising therapeutic target for liver aging and associated steatosis.
摘要：
肝脏脂肪变性,非酒精性脂肪性肝病（NAFLD）发展的第一步，在人口老龄化中经常观察到。然而,潜在的分子机制在很大程度上仍然未知。在这项研究中,我们首先采用GSEA富集分析来鉴定短链酰基辅酶A脱氢酶（SCAD），参与脂肪酸的线粒体β-氧化，可能与老年人的肝脂肪变性有关。随后，我们检测了各种老年人类和小鼠的SCAD表达和肝脏甘油三酯含量,发现老年肝脏中甘油三酯显著升高,而SCAD上调.我们在SCAD消融小鼠中的进一步证据表明，SCAD缺失能够减缓肝脏衰老并改善衰老相关的脂肪肝。对SCAD缺失减轻脂肪变性的分子途径的检查表明，脂滴的自噬降解，在老年野生型小鼠中没有检测到，在缺乏SCAD的老年小鼠中保持。这是由于乙酰辅酶A（乙酰辅酶A）的产量减少，在老野生型小鼠的肝脏中含量丰富。总之,我们的研究结果表明,抑制SCAD可能通过促进脂肪吞噬来预防年龄相关性肝脂肪变性,并且SCAD可能是治疗肝脏老化和相关脂肪变性的有前景的治疗靶点.
