Dysfunctional VLDL metabolism in MASLD

Fig. 1. Multifaceted regulation of VLDL synthesis and export by S-adenosylmethionine. See text for a description. BHMT betaine-homocysteine methyltransferase, CCT, CTP phosphocholine cytidylyltransferase, CDP-CH CDP-choline, CH choline, CHDH choline dehydrogenase, CHPT choline phosphate transferase, CK choline kinase, DG diglycerides, GATOR1 GTPase-activating protein activity toward Rag 2, GDE1 glycerophosphocholine phosphodiesterase 1, GPC glycerophosphocholine, Hcy homocysteine, LPC lysophosphatidylcholine, MAT1A methionine adenosyltransferase 1A, Met methionine, mTORC1 mechanistic target of rapamycin kinase 1, PC phosphatidylcholine, PE phosphatidylethanolamine, PEMT phosphatidylethanolamine N-methyltransferase, PNPLA7 lysophosphatidylcholine phospholipase, PNPLA8 phosphatidylcholine phospholipase, PRMT1 protein methyltransferase 1, SAMe S-adenosylmethionine, SAMTOR SAMe sensor upstream of mTORC1, TG triglycerides, VLDL very low-density lipoproteins.

Fig. 2. Diversity in MASLD: unveiling subtypes. Unsupervised statistical analysis classified MASLD patients into distinct subtypes or “metabotypes” based on their serum lipidomic profiles, obtained using mass spectrometry (MS), with two primary classifications: MASLD-A metabotype, characterized by lower serum VLDL levels and associated with reduced cardiovascular disease (CVD) risk; and MASLD-C metabotype, featuring increased VLDL levels and linked to elevated CVD risk. An intermediate MASLD-B metabotype was identified, showcasing a combination of features.

Fig. 3. Association between sample size and GWAS discoveries in metabolic diseases. X-axis: effective sample size of GWAS studies based on the number of cases and controls used in each study. Y-axis: number of independent associations discovered in each study. Both axes are in logarithmic scale. We used the GWAS Catalog to identify studies for four metabolic diseases, namely MASLD, T2DM, CVD, and CKD. As a quality control, we selected only GWAS fulfilling four criteria, namely: i) including at least 1000 cases and 1000 controls, ii) studying individuals of a single genetic ancestry (e.g. East Asians), iii) performing association tests focused exclusively on additive effects, and iv) testing markers spread genome-wide (e.g. exome studies excluded). In total, 37 studies passed these filters: six studies for MASLD and 31 for the other three diseases (red and gray points, respectively). The dashed lines indicate the regression line for each subgroup.