LaPoint Andrew, Singer Jason M, Ferguson Daniel, Shew Trevor M, Renkemeyer M Katie, Palacios Hector, Field Rachael, Shankaran Mahalakshmi, Smith Gordon I, Yoshino Jun, He Mai, Patti Gary J, Hellerstein Marc K, Klein Samuel, Brestoff Jonathan R, Finck Brian N, Lutkewitte Andrew J
bioRxiv. 2023 Feb 3:2023.02.01.526676. doi: 10.1101/2023.02.01.526676.
Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue expression is decreased in people with obesity compared to lean subjects and low expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of nonalcoholic steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health and its loss predisposes mice to nonalcoholic steatohepatitis.
功能失调的脂肪组织被认为会促进肝脂肪变性和全身性胰岛素抵抗的发展，但其中涉及的许多机制仍不清楚。Lipin 1催化磷脂酸转化为二酰甘油（DAG），这是甘油三酯合成的倒数第二步，对脂质储存至关重要。在此我们发现，与瘦人相比，肥胖人群的脂肪组织表达降低，且低表达与多组织胰岛素抵抗以及肝脏从头脂肪生成率增加相关。综合代谢和多组学表型分析表明，脂肪细胞特异性缺失Lipin 1的小鼠具有代谢不健康的表型，包括肝脏和骨骼肌胰岛素抵抗、肝脂肪变性、肝脏从头脂肪生成增加以及非酒精性脂肪性肝炎的转录组特征，而高脂饮食会加剧这种情况。我们得出结论，脂肪细胞Lipin 1介导的脂质储存对于维持脂肪组织和全身代谢健康至关重要，其缺失会使小鼠易患非酒精性脂肪性肝炎。
