Does visceral adiposity drive MASLD by increasing portal free fatty acid delivery?

Visceral adiposity is a critical driver of metabolic dysfunction-associated steatotic liver disease (MASLD), operating through direct anatomical and metabolic pathways that deliver excess lipids directly to the liver.

Mechanistic explanations of portal flux

Visceral adipose tissue (VAT) is highly lipolytically active and anatomically unique because it drains directly into the portal vein. In states of visceral adiposity, VAT becomes highly insulin-resistant, accelerating the rate of lipolysis and releasing high concentrations of free fatty acids (FFAs) directly into the portal circulation. Tracer and hepatic catheterization studies confirm that this elevated portal FFA flux provides a major portion of the lipid substrates utilized by hepatocytes. This direct, high-volume delivery of fatty acids promotes rapid hepatic triglyceride accumulation and hepatocellular lipid loading. Furthermore, visceral adiposity leads to an altered adipokine and cytokine profile—specifically a reduction in adiponectin and an elevation of pro-inflammatory cytokines—which acts directly on hepatocytes via the portal pathway to promote inflammation.

Clinical and metabolic implications

The continuous influx of portal FFAs, particularly saturated species such as palmitate, impairs insulin receptor signaling within hepatocytes, leading to hepatic insulin resistance. This resistance impairs the liver's ability to regulate glucose and lipid metabolism, compounding metabolic dysfunction. Hepatic triglyceride accumulation serves as the foundational "first hit" and central hallmark of MASLD. The resulting lipotoxicity, combined with localized portal-driven inflammation and insulin resistance, establishes the complete pathophysiology of MASLD, predisposing individuals to progressive steatohepatitis and hepatic fibrosis.

Bottom line

• Visceral adiposity directly increases the delivery of free fatty acids and inflammatory cytokines to the liver via portal circulation, promoting hepatic triglyceride accumulation and hepatic insulin resistance, which together drive the development and progression of MASLD physiology.