HILPDA induces development of NASH-driven HCC

Hepatic hypoxia-inducible lipid droplet associated protein (HILPDA) is predictive of survival in patients with nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC), according to a study.

Immunohistochemistry and transcriptomics analyses were carried out to examine the clinical significance of HILPDA in human NASH-driven HCC specimens. The authors analysed the oncogenic effect of HILPDA in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia.

Shotgun and targeted approaches were used to assess lipidomics profiling of wild-type and HILPDA knockout HCC cells. In addition, wild-type (Hilpda^fl/fl) and hepatocyte-specific Hilpda knockout (Hilpda^ΔHep) mice were provided a Western diet and given high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC.

Upregulated HILPDA expression in patients with NASH-driven HCC showed a robust association with poor survival. HILPDA in oxygen-deprived and lipid-loaded culture conditions also raised the possibility of human hepatoma cells and growth of 3D epithelial spheroids.

On the other hand, lack of HILPDA resulted in a flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, which exacerbated lipid peroxidation and apoptosis in hypoxia. Pharmacological inhibition of ceramide synthesis reversed the HILPDA deficiency-induced apoptosis.

In the experimental mouse model of NASH-drive HCC, Hilpda^ΔHep showed a decreased hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. In single-cell analysis, hepatic HILPDA played a dual role of protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH.

“Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target,” the authors said.