Genetically determined expression of lipoprotein lipase is linked to hepatocellular carcinoma in alcohol-associated cirrhosis

Background Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoproteinlipase (LPL) gene is linked to non-alcoholic fatty liver disease, but LPL is not expressed in healthy liver. We aimed at clarifying its role in ALD.

Methods Patients with alcohol-associated cirrhosis, with (n=385) and without hepatocellular carcinoma (HCC) (n=656), with HCC due to viral hepatitis C (n=280), controls with alcohol abuse but without liver damage (n=366) and healthy controls (n=277) were genotyped for the LPL rs13702 polymorphism. LPL mRNA expression in human liver specimen and in liver cell lines was investigated. Results Frequency of the LPL rs13702 CC genotype was lower in ALD patients with HCC in comparison to ALD patients without HCC both in the initial and the validation cohort (3.9% vs. 9.3% and 4.7% vs. 9.5%; p<0.05 each), compared to patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%) or healthy controls (9.0%). This protective effect (OR=0.5) was confirmed in multivariate analysis including age (OR=1.1/year), male sex (OR=3.0), diabetes (OR=1.8), and carriage of the PNPLA3 I148M risk variant (OR=2.0). Similar effects were seen on population level in the UK Biobank cohort. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with alcohol-associated cirrhosis compared to controls and alcohol-associated HCC. While hepatocyte cell lines showed negligible LPL expression, hepatic stellate cells expressed LPL, with increase after pioglitazone stimulation.

Conclusion The LPL rs13702 CC genotype confers protection against HCC in ALD.

Publication History

Article published online:
18 January 2023