Endocrine Abstracts

The I148M variant in PNPLA3 alone explains 10% of the risk of cirrhosis (UK Biobank). Of all subjects, 30-50% are heterogenous for the PNPLA3 I148M variant. Both MAFLD associated with insulin resistance (IR) (‘MASLD-IR’) and MAFLD caused by the PNPLA3 I148M variant (’MASLD-PNPLA3’) predispose to all stages of MASLD. Patients with both IR and the PNPLA3 I148M variant are at particularly high risk of liver disease. IR increases while the PNPLA3 I148M variant decreases the risk of cardiovascular disease. This implies that the pathogenesis of ‘MASLD-IR’ and ‘MASLD-PNPLA3’ differ. Substrate excess. In ‘MASLD-IR’ compared to age-, gender,- and BMI-matched controls, there is, perhaps simply because of overeating and inactivity, marked substrate excess (glucose, fatty acids, amino acids) while substrates are unaltered in ’MASLD-PNPLA3’. Substrate fluxes. A dipose tissue lipolysis and de novo lipogenesis (DNL) are the two most important pathways contributing to steatosis in ‘MASLD-IR’. DNL is low and lipolysis unaltered in ‘MASLD-PNLA3’. Hepatic TG accumulation is thus purely a consequence of PNPLA3-I148M-induced changes in intrahepatic metabolism. Human liver and adipose tissue lipidome. The human liver lipidome in ‘MASLD-IR’ compared to matched controls is markedly enriched with saturated TGs and IR inducing ceramides. In PNPLA3 I148M carriers vs, non-carriers, the relative and absolute amounts of polyunsaturated fatty acids (PUFAs) in TGs are markedly enriched and there are no changes in bioactive lipids consistent with lack of insulin resistance in ‘MASLD-PNPLA3’. The increase in PUFAs is due to retention of PUFAs in hepatic TGs. Circulating lipids. >‘MASLD-IR’ is characterized by increased circulating VLDL and low HDL. In IR individuals carrying the PNPLA3 variant, opposite, anti-atherogenic changes are observed. Conclusions. MASLD is more complex than its simple definition suggests. This knowledge has implications in the clinic for prediction of the individual risk of future liver and cardiovascular events and choice of therapies.