Apolipoprotein C-III in association with metabolic-dysfunction associated steatotic liver disease: A large, multicenter study

Background & aims: The available literature on the effect of apolipoprotein C-III (ApoC-III) inhibition in MASLD reveals inconsistencies. The aim of the present work was to examine levels of ApoC-III in the entire spectrum of metabolic-dysfunction associated steatotic liver disease (MASLD).

Methods: This is a multicenter study involving patients enrolled in two gastroenterology-hepatology clinics (Greece and Australia) and in a bariatric-metabolic surgery clinic (Italy), with liver biopsy before and after bariatric surgery or lifestyle modification.

Results: Comparing simple MASL to steatohepatitis (MASH) with fibrosis stage F ≥ 2 (at-risk MASH), revealed a marginally significant trend for decreased ApoC-III levels in the latter group (p = 0.07). Multi-adjusted analysis revealed an inverse association between ApoC-III and at-risk MASH (Odds Ratio_{per 1 mg/dL increase in ApoC-III} = 0.91, 95 % Confidence Interval (0.83, 0.99)). ApoC-III interacted with triglycerides in predicting at-risk MASH (p-for-interaction = 0.002). Participants with ApoC-III > median (∼3.75 mg/dL) and normal triglycerides (triglyceridese≤150 mg/dL) had the lowest likelihood to present at-risk MASH (31.8 %) in contrast with participants with ApoC-III < median and hypertriglyceridemia among whom at-risk MASH was recorded in 57.1 %. In multi-adjusted analysis participants with normal triglycerides and high ApoC-III had 64 % lower odds of at-risk MASH compared with their counterparts with ApoC-III < median (OR = 0.36, 95%CI (0.14, 0.86)). Among participants with hypertriglyceridemia, those with ApoC-III < median had less prevalent at-risk MASH compared with those with ApoC-III ≥ median (OR = 0.54, 95%CI (0.32, 0.98)); however in all cases significance was lost when liver enzymes were taken into account.

Conclusions: In advanced disease stages, ApoC-III levels seem to be decreased and advanced organ damage may be a potential explanation. Mendelian randomization studies are needed to confirm or refute this hypothesis.