Adipose tissue dysfunction and the liver: reframing MASH as the hepatic expression of systemic metabolic dysfunction

Metabolic dysfunction-associated steatohepatitis (MASH) is conventionally investigated and treated as a primary disease of the liver. In type 2 diabetes, however, the hepatic lesion is best understood as the visible endpoint of a systemic disorder of adipose tissue. This review develops the mechanistic case for that reading. We trace a single causal narrative: from adipose tissue dysfunction (ATD), the immuno-inflammatory and endocrine failure of dysfunctional adipose tissue, through a reconfigured adipokine secretome and adipose inflammation, to selective insulin resistance and a systemic loss of metabolic flexibility, and thence to the lipid and inflammatory burden that the liver, by virtue of its portal anatomy and metabolic role, is uniquely exposed to. Within this framework, hepatic steatosis is the expected consequence of failed peripheral lipid buffering, and steatohepatitis the readout of lipotoxic, immunometabolic injury rather than an autonomous hepatic process. We argue that MASH is more faithfully interpreted as the hepatic expression of systemic adipose tissue dysfunction than as a primary liver disease, and that this reframing relocates both mechanistic enquiry and the most rational point of therapeutic intervention upstream, to adipose biology and fuel handling. We propose adipose dysfunction as a major, phenotype-dependent upstream driver of T2D-associated MASH that interacts bidirectionally with hepatic, genetic and gut-derived mechanisms, rather than as its sole, universal or unidirectional cause. The argument is advanced as a biologically coherent framework intended to inform how the disorder is conceived and studied.