Steinberg Gregory R, Valvano Celina M, De Nardo William, Watt Matthew J
Centre for Metabolism, Obesity and Diabetes Research, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
Centre for Metabolism, Obesity and Diabetes Research, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
J Hepatol. 2025 Mar 1. doi: 10.1016/j.jhep.2025.02.033.
The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol and non-esterified fatty acids from white adipose tissue, influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation caused by obesity, insulin resistance, and type 2 diabetes disrupts these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). In this review, we explore the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis, dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. We also highlight the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.
肝脏作为一个核心代谢枢纽，整合来自胃肠道和脂肪组织的信号，以调节碳水化合物、脂质和氨基酸代谢。肠道衍生的代谢产物，如乙酸盐、乙醇以及白色脂肪组织中的非酯化脂肪酸，会影响肝脏过程，而这些过程依赖线粒体功能来维持全身能量平衡。由肥胖、胰岛素抵抗和2型糖尿病引起的代谢失调会破坏这些途径，导致代谢功能障碍相关脂肪性肝病（MASLD）和脂肪性肝炎（MASH）。在本综述中，我们探讨了肠道-脂肪组织-肝脏轴内的代谢通量，重点关注从头脂肪生成、葡萄糖和果糖等膳食底物以及MASLD进展过程中线粒体功能变化的关键作用。我们还强调了白色脂肪组织胰岛素抵抗和线粒体动力学受损对肝脏脂质积累的影响。进一步了解胃肠道底物通量与脂肪组织之间的相互作用如何与肝脏线粒体的结构和功能改变相互交织，对于确定新的治疗靶点以及推进MASLD和MASH的治疗至关重要。
