Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis.
Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis.
复制标题
脂肪组织过氧化物酶体脂质合成通过 LXR 依赖性脂肪生成协调肥胖和胰岛素抵抗。
DOI：
10.1016/j.molmet.2024.101913
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发表时间：
2024
影响因子：
8.1
通讯作者：
Lodhi,IrfanJ
中科院分区：
文献类型：
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作者：
Kleiboeker,Brian;He,Anyuan;Tan,Min;Lu,Dongliang;Hu,Donghua;Liu,Xuejing;Goodarzi,Parniyan;Hsu,Fong-Fu;Razani,Babak;Semenkovich,ClayF;Lodhi,IrfanJ
目的脂肪组织质量是由脂肪分解和脂肪储存之间的平衡维持的。脂肪组织脂肪生成对脂肪量的贡献，特别是在高脂肪喂养的情况下，被认为是次要的。在这里，我们研究了脂肪特异性失活过氧化物酶体脂合成蛋白peexrap对脂肪酸合成酶（FASN）介导的脂肪生成的影响及其对肥胖和代谢稳态的影响。方法为了探索PexRAP在脂肪组织中的作用，我们对脂肪特异性敲除PexRAP的小鼠进行了代谢表型分析。大量RNA测序用于确定对peexrap缺失的转录组反应，14c -丙二醇辅酶a使我们能够测量这些小鼠脂肪组织中的新生脂肪生成活性。体外细胞培养模型用于阐明细胞对peexrap缺失的反应机制。结果PexRAP缺失通过激活新生脂肪生成促进饮食诱导的肥胖和胰岛素抵抗。从机制上讲，peexrap失活抑制了碳向乙醇胺缩醛原的通量。这增加了细胞核PC/PE比率，促进了胆固醇错定位，导致肝脏X受体（LXR）的激活，这种核受体已知会因细胞内胆固醇升高而激活。LXR激活导致磷脂重塑酶LPCAT3的表达增加，诱导fasn介导的脂肪生成，从而促进饮食诱导的肥胖和胰岛素抵抗。这些研究揭示了过氧化物酶体衍生的脂质在调节lxr依赖性脂肪生成中的意想不到的作用，并表明脂肪生成的激活，加上膳食脂质过载，加剧了肥胖和代谢失调。
ObjectiveAdipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis.MethodsTo explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and14C-malonyl CoA allowed us to measure de novo lipogenic activity in adipose tissue of these mice. In vitro cell culture models were used to elucidate the mechanism of cellular responses to PexRAP deletion.ResultsAdipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance.ConclusionsThese studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.