Lambert Jennifer E, Ramos-Roman Maria A, Valdez Maressa J, Browning Jeffrey D, Rogers Thomas, Parks Elizabeth J
Center for Human Nutrition.
Department of Internal Medicine.
J Clin Invest. 2025 May 1;135(9). doi: 10.1172/JCI174233.
BACKGROUNDLipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction-associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway.METHODSOverweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by 1H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG.RESULTSBody weight loss (-10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% (P = 0.02) because of a 67% reduction in contribution from lipogenesis (P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG.CONCLUSIONThese data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies.TRIAL REGISTRATIONClinicalTrials.gov (NCT01371396).FUNDINGNational Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.
背景
在代谢功能障碍相关脂肪性肝病（MASLD）中，脂肪生成在肝内甘油三酯（IHTG）的病理性蓄积中起重要作用。由于肝脏脂肪生成对能量摄入高度敏感，我们推测体重减轻诱导的MASLD缓解机制将由脂肪生成途径的显著减少驱动。
方法
肝脏脂肪含量高（HighLF；n = 9；通过1H磁共振波谱测量IHTG≥5.6%）或低（正常）肝脏脂肪（LowLF；n = 6；IHTG < 5.6%）的超重成年人接受了6个月的饮食咨询，并在住院研究期间进行了全面的代谢表型分析，包括空腹和进食状态。使用多种稳定同位素评估脂肪生成、游离脂肪酸（FFA）和膳食脂肪对IHTG的贡献。
结果
体重减轻（-10%±2%）使MASLD患者的IHTG降低（从19.4%±3.6%降至4.5%±2.1%，P < 0.001）。胰岛素敏感性显著改善（46%，P < 0.01），而来自脂肪组织的空腹FFA通量没有差异。极低密度脂蛋白甘油三酯（VLDL-TG）浓度下降了38%（P = 0.02），原因是脂肪生成的贡献减少了67%（P = 0.02），而FFA和膳食脂肪对VLDL-TG的绝对贡献没有差异。脂肪生成减少与IHTG的降低显著相关。
结论
这些数据强调了脂肪生成在MASLD病理中的主要作用，并突出了通过治疗策略控制该途径的重要性。
试验注册
ClinicalTrials.gov（NCT01371396）。
资助
美国国立卫生研究院（NIH）资助RL1DK081187；西南肥胖研究特别工作组（TORS）NIH UL1DE019584；以及临床和转化科学奖NIH/国家推进转化科学中心UL1-RR024982。
