LaPoint Andrew, Singer Jason M, Ferguson Daniel, Shew Trevor M, Renkemeyer M Katie, Palacios Hector H, Field Rachael L, Yerrathota Sireesha, Kumari Roshan, Shankaran Mahalakshmi, Smith Gordon I, Yoshino Jun, He Mai, Patti Gary J, Hellerstein Marc K, Klein Samuel, Brestoff Jonathan R, Morris E Matthew, Finck Brian N, Lutkewitte Andrew J
Department of Medicine and.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Clin Invest. 2024 Oct 15;134(23):e169722. doi: 10.1172/JCI169722.
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, the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared with lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multiomic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated 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 metabolically associated steatohepatitis.
功能失调的脂肪组织被认为会促进肝脂肪变性和全身胰岛素抵抗的发展，但其中涉及的许多机制仍不清楚。脂联素1催化磷脂酸转化为二酰甘油，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，肥胖人群脂肪组织中LPIN1的表达降低，且低LPIN1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Lpin1基因敲除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代谢相关脂肪性肝炎的转录组特征，高脂饮食会加剧这种情况。我们得出结论，脂肪细胞脂联素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，其缺失使小鼠易患代谢相关脂肪性肝炎。
