In advanced human alcohol-related liver disease, proceramide gene expression is increased across multiple biosynthetic pathways—including CerS1, CerS5, CerS6, and SPTLC1—and sphingomyelinase activity is elevated, while ceramide degradation via CERD2 is reduced, indicating a shift toward ceramide accumulation.

Alcohol exposure causes liver cells to produce more ceramides by activating enzymes that build them from scratch and break down other fats into ceramides, while simultaneously reducing the enzymes that break down ceramides. This leads to a buildup of ceramides inside liver cells, which damages the internal factory that makes proteins, triggers cell death, and disrupts how the liver responds to insulin.