The role of PNPLA3 and MBOAT7 during alcohol detoxification: Different mechanisms for fibrosis development

Background and Aims:

In genome wide association studies PNPLA3 and MBOAT7 were identified as important risk genes for the development of alcoholic cirrhosis, however, their functions and molecular mechanisms are still poorly understood. We here present first data on the role of PNPLA3 and MBAOT7 genotypes on liver stiffness (LS), steatosis (CAP) and inflammation during alcohol withdrawal.

Method:

763 patients with ALD which were hospitalized for alcohol withdrawal at Salem Medical Center between 2007 and 2018 were genotyped for PNPLA3 s738409 and MBOAT7 rs626283 polymorphisms. All patients had routine laboratory, abdominal ultrasound and a transient elastography measurement (FibroScan) at admission. In 512 patients, data after 6.3 days of alcohol withdrawal was available.

Results:

71% of the patients were male, median age was 52 years, median BMI was 24.7 kg/m2 and median alcohol consumption was 163 g/day. At admission, no difference between the genotypes of PNPLA3 and MBOAT7 was seen regarding age, BMI, gender, alcohol consumption or transaminase levels. Significant differences were observed for PNPLA3 and MBOAT7 during alcohol detoxification. While MBOAT7 was associated with higher LS, no differences were observed between genotypes upon alcohol detoxification. In contrast, PNPLA3 caused clearly a delayed resolution of LS during withdrawal of alcohol due to inflammation. This could be recapitulated when looking at serum markers of liver inflammation. In a sub-analysis of n = 108 liver biopsies, inflammation was highly associated with PNPLA3 but not MBOAT7. More interestingly, PNPLA3 was associated with higher steatosis (CAP) although it resolved faster upon detoxification. No effect at all was seen for MBOAT7 on steatosis. A multivariate model confirmed that PNPLA3 was associated with steatosis and inflammation but not fibrosis. MBOAT7 was only associated with fibrosis/cirrhosis but not inflammation or steatosis.

Conclusion:

These first genotype data on a "human alcohol knock-out" intervention underscore important differences between PNPLA3 and MBOAT7. PNPLA3 seems to primarily drive fibrosis through inflammation and our data on CAP suggest an enhanced fat metabolism. In contrast, MBOAT7 seems to have a direct effect on fibrosis signaling and is neither associated with steatosis nor inflammation. Finally, alcohol detoxification could be a novel interventional approach to further dissect metabolic mechanisms and their associations with genotypes.