Aging-induced short-chain acyl-CoA dehydrogenase promotes age-related hepatic steatosis by suppressing lipophagy

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Aging Cell Pub Date : 2024-06-19 DOI:10.1111/acel.14256
Dan Deng, Shanshan Yang, Xiaoqian Yu, Ruixue Zhou, Yin Liu, Hongmei Zhang, Daxin Cui, Xingrong Feng, Yanting Wu, Xiaocun Qi, Zhiguang Su
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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.

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衰老诱导的短链酰基-CoA脱氢酶通过抑制噬脂作用促进与衰老相关的肝脂肪变性。
肝脏脂肪变性是非酒精性脂肪肝(NAFLD)发病的第一步,在老龄人口中经常出现。然而,其潜在的分子机制在很大程度上仍然未知。在本研究中,我们首先利用 GSEA 富集分析鉴定了短链酰基-CoA 脱氢酶(SCAD),它参与线粒体脂肪酸的β-氧化,可能与老年人的肝脂肪变性有关。随后,我们研究了 SCAD 在不同年龄的人和小鼠中的表达和肝脏甘油三酯含量,发现甘油三酯明显增加,SCAD 在老年肝脏中上调。我们在SCAD缺失小鼠中得到的进一步证据表明,SCAD缺失能够延缓肝脏衰老并改善衰老相关性脂肪肝。对SCAD缺失减轻脂肪肝的分子途径的研究发现,在野生型老年小鼠中检测不到的脂滴自噬降解在SCAD缺失的老年小鼠中得以维持。这是由于野生型老年小鼠肝脏中含量丰富的乙酰辅酶 A(acetyl-CoA)生成减少所致。总之,我们的研究结果表明,抑制 SCAD 可通过促进脂肪吞噬来预防年龄相关性肝脂肪变性,SCAD 可能是治疗肝脏衰老和相关脂肪变性的一个很有前景的靶点。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
期刊最新文献
Issue Information Featured Cover Correction to ‘Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis’ RETRACTION: 1,25-Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2-antioxidant signaling and inactivation of p16/p53-senescence signaling Issue Information
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