This review frames , fatty acid overload, and selective hepatic insulin resistance as central, modifiable mechanisms in progression.
Evidence
The evidence is a mechanistic and clinical review of MASLD pathways, including hepatic triglyceride accumulation, lipotoxic intermediates, zonal and non-classical insulin signaling, mTORC1 and protein kinase C pathways, and emerging pharmacologic agents such as resmetirom.
Caveat
The article synthesizes mechanisms and treatment implications rather than testing a single intervention, and it emphasizes that sustained lifestyle-driven weight loss remains the cornerstone despite promising drugs.
Simplified
(MASLD) represents a progressive spectrum ranging from simple hepatic steatosis to steatohepatitis and fibrosis. Although insulin resistance (IR) plays a central role in metabolic diseases, in the liver, insulin- or substrate-driven (DNL) promotes triglyceride accumulation through multiple complex regulatory mechanisms, including specific transcription factors, regardless of whether IR is primary or not. Elevated free fatty acids, resulting from increased adipose lipolysis, further augment hepatic lipid storage and contribute to IR and the progression of MASLD through lipotoxic intermediates such as diacylglycerols and ceramides, as well as other pathways. Numerous studies have identified DNL as a major, yet modifiable, contributor to MASLD. In addition, zonal differences in hepatic insulin signaling, non-classical insulin signaling pathways, and activation of the mechanistic target of rapamycin complex 1 and protein kinase C pathways appear to be involved in the development of selective hepatic IR. Recently, new pharmacologic agents, including resmetirom, have shown promise in improving steatohepatitis and fibrosis in MASLD. Nevertheless, sustained weight loss through lifestyle modification remains the cornerstone of MASLD prevention and therapy. Further mechanistic understanding of how IR and substrate overload promote DNL and hepatic fat accumulation is critical for developing effective treatments for MASLD.
Key numbers
55%
Projected prevalence of
Current prevalence is approximately 40%, projected to exceed this by 2040.
3.5×
Contribution of to VLDL-TG in H-LF individuals
Individuals with high liver fat have a 3.5× greater contribution of to VLDL-TG than those with low liver fat.
Full Text
We can’t show the full text here under this license.
