Dysfunctional VLDL metabolism in MASLD
Hodson, L. & Gunn, P. J. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat. Rev. Endocrinol. 15, 689–700 (2019).
Google Scholar
Guillou, H., Zadravec, D., Martin, P. G. & Jacobsson, A. The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog. Lipid Res. 49, 186–199 (2010).
Google Scholar
Wang, Y. et al. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J. Lipid Res. 47, 2028–2041 (2006).
Google Scholar
Wang, Y. et al. Transcriptional regulation of hepatic lipogenesis. Nat. Rev. Mol. Cell Biol. 16, 678–689 (2015).
Google Scholar
Wishart, D. S. et al. HMDB 5.0: the Human Metabolome Database for 2022. Nucleic Acids Res. 50, D622–D631 (2022).
Google Scholar
Quehenberger, O. et al. Lipidomics reveals a remarkable diversity of lipids in human plasma. J. Lipid Res. 51, 3299–3305 (2010).
Google Scholar
Psychogios, N. et al. The human serum metabolome. PLoS One 6, e16957 (2011).
Google Scholar
Masoodi, M. et al. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat. Rev. Gastroenterol. Hepatol. 18, 835–856 (2021).
Google Scholar
Alonso, C. et al. Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis. Gastroenterology 152, 1449–1461.e7 (2017).
Google Scholar
Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 78, 1966–1986 (2023).
Google Scholar
Arab, J. P., Arrese, M. & Trauner, M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. Annu. Rev. Pathol. 13, 321–350 (2018).
Google Scholar
Le, M. H. et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clin. Mol. Hepatol. 28, 841–850 (2022).
Google Scholar
Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335–1347 (2023).
Google Scholar
De, A. et al. Lean Indian patients with non-alcoholic fatty liver disease (NAFLD) have less metabolic risk factors but similar liver disease severity as non-lean patients with NAFLD. Int J. Obes. 47, 986–992 (2023).
Google Scholar
Zadoorian, A., Du, X. & Yang, H. Lipid droplet biogenesis and functions in health and disease. Nat. Rev. Endocrinol. 19, 443–459 (2023).
Google Scholar
Ipsen, D. H., Lykkesfeldt, J. & Tveden-Nyborg, P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol. Life Sci. 75, 3313–3327 (2018).
Google Scholar
Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).
Google Scholar
Mato, J. M., Alonso, C., Noureddin, M. & Lu, S. C. Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease. World J. Gastroenterol. 25, 3009–3020 (2019).
Google Scholar
Heeren, J. & Scheja, L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol. Metab. 50, 101238 (2021).
Google Scholar
Martínez-Uña, M. et al. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis. Hepatology 58, 1296–1305 (2013).
Google Scholar
van der Veen, J. N. et al. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta Biomembr. 1859, 1558–1572 (2017).
Google Scholar
Vance, D. E. Phospholipid methylation in mammals: from biochemistry to physiological function. Biochim. Biophys. Acta 1838, 1477–1487 (2014).
Google Scholar
Hirabayashi, T. et al. Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups. Cell Rep. 42, 111940 (2023).
Google Scholar
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
Google Scholar
Jiang, C. et al. PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2. Cell Metab. 35, 2183–2199.e7 (2023).
Google Scholar
Quinn, W. J. et al. mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion. J. Clin. Invest. 127, 4207–4215 (2017).
Google Scholar
Uehara, K. et al. Activation of Liver mTORC1 Protects Against NASH via Dual Regulation of VLDL-TAG Secretion and De Novo Lipogenesis. Cell Mol. Gastroenterol. Hepatol. 13, 1625–1647 (2022).
Google Scholar
Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).
Google Scholar
Mudd, S. H. et al. Methyl balance and transmethylation fluxes in humans. Am. J. Clin. Nutr. 85, 19–25 (2007).
Google Scholar
Hoffman, D. R., Marion, D. W., Cornatzer, W. E. & Duerre, J. A. S-Adenosylmethionine and S-adenosylhomocysteine metabolism in isolated rat liver. Effects of L-methionine, L-homocysteine, and adenosine. J. Biol. Chem. 255, 10822–10827 (1980).
Google Scholar
Lu, S. C. et al. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc. Natl Acad. Sci. USA 98, 5560–5565 (2001).
Google Scholar
Martínez-Chantar, M. L. et al. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J. 16, 1292–1294 (2002).
Google Scholar
Cano, A. et al. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology 54, 1975–1986 (2011).
Google Scholar
Lu, S. C. & Mato, J. M. S-adenosylmethionine in liver health, injury, and cancer. Physiol. Rev. 92, 1515–1542 (2012).
Google Scholar
Ahrens, M. et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 18, 296–302 (2013).
Google Scholar
Murphy, S. K. et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 145, 1076–1087 (2013).
Google Scholar
Moylan, C. A. et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology 59, 471–482 (2014).
Google Scholar
Guo, T. et al. S-adenosylmethionine upregulates the angiotensin receptor-binding protein ATRAP via the methylation of HuR in NAFLD. Cell Death Dis. 12, 306 (2021).
Google Scholar
Orešič, M. et al. Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids. Diabetologia 56, 2266–2274 (2013).
Google Scholar
Noureddin, M. et al. Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF). Hepatology 79, 135–148 (2024).
Google Scholar
Hagström, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).
Google Scholar
Sanyal, A. J. et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 385, 1559–1569 (2021).
Google Scholar
Martínez-Arranz, I. et al. Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles. Hepatology 76, 1121–1134 (2022).
Google Scholar
Arvind, A. et al. Risk of Cardiovascular Disease in Individuals With Nonobese Nonalcoholic Fatty Liver Disease. Hepatol. Commun. 6, 309–319 (2022).
Google Scholar
Qin, W. et al. Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low-density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen. J. Biol. Chem. 286, 27769–27780 (2011).
Google Scholar
Sookoian, S., Pirola, C. J., Valenti, L. & Davidson, N. O. Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology. Hepatology 72, 330–346 (2020).
Google Scholar
Romeo, S., Sanyal, A. & Valenti, L. Leveraging Human Genetics to Identify Potential New Treatments for Fatty Liver Disease. Cell Metab. 31, 35–45 (2020).
Google Scholar
Newberry, E. P. et al. Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer. Hepatology 74, 1203–1219 (2021).
Google Scholar
Newberry, E. P., Strout, G. W., Fitzpatrick, J. A. J. & Davidson, N. O. Liver-specific deletion of Mttp versus Tm6sf2 reveals distinct defects in stepwise VLDL assembly. J. Lipid Res. 62, 100080 (2021).
Google Scholar
Morrison, M. C. et al. Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr-/-.Leiden Mice. Hepatol. Commun. 2, 1513–1532 (2018).
Google Scholar
Stine, J. G. et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharm. Ther. 48, 696–703 (2018).
Google Scholar
Newberry, E. P. et al. Impaired Hepatic Very Low-Density Lipoprotein Secretion Promotes Tumorigenesis and Is Accelerated with Fabp1 Deletion. Am. J. Pathol. (2024).
Wang, G., Bonkovsky, H. L., de Lemos, A. & Burczynski, F. J. Recent insights into the biological functions of liver fatty acid binding protein 1. J. Lipid Res. 56, 2238–2247 (2015).
Google Scholar
Newberry, E. P., Xie, Y., Kennedy, S. M., Luo, J. & Davidson, N. O. Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. Hepatology 44, 1191–1205 (2006).
Google Scholar
Newberry, E. P. et al. Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice. Hepatology 65, 836–852 (2017).
Google Scholar
Loomba, R., Friedman, S. L. & Shulman, G. I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537–2564 (2021).
Google Scholar
Li, Y. et al. Hepatic lipids promote liver metastasis. JCI Insight 5, e136215 (2020).
Google Scholar
Wang, Z. et al. Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Cell Metab. 35, 1209–1226.e13 (2023).
Google Scholar
Hayes, J. D., Dinkova-Kostova, A. T. & Tew, K. D. Oxidative Stress in Cancer. Cancer Cell 38, 167–197 (2020).
Google Scholar
Fan, W. et al. Hepatic prohibitin 1 and methionine adenosyltransferase α1 defend against primary and secondary liver cancer metastasis. J. Hepatol. 80, 443–453 (2024).
Google Scholar
Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet 40, 1461–1465 (2008).
Google Scholar
Trépo, E. & Valenti, L. Update on NAFLD genetics: From new variants to the clinic. J. Hepatol. 72, 1196–1209 (2020).
Google Scholar
Anstee, Q. M. et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. J. Hepatol. 73, 505–515 (2020).
Google Scholar
Chen, Y. et al. Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease. Nat. Genet 55, 1640–1650 (2023).
Google Scholar
Luukkonen, P. K. et al. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight 4, e127902 (2019).
Google Scholar
Luukkonen, P. K. et al. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J. Hepatol. 65, 1263–1265 (2016).
Google Scholar
Luukkonen, P. K. et al. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proc. Natl Acad. Sci. USA 120, e2217543120 (2023).
Google Scholar
Jamialahmadi, O. et al. Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease. Gastroenterology 160, 1634–1646 (2021).
Google Scholar
Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506–514 (2015).
Google Scholar
Burkhardt, R. et al. Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J. Clin. Invest. 120, 4410–4414 (2010).
Google Scholar
Berriot-Varoqueaux, N. et al. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu. Rev. Nutr. 20, 663–697 (2000).
Google Scholar
Beer, N. L. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18, 4081–1088 (2009).
Google Scholar
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Google Scholar
Zhang, Y., Qi, G., Park, J. H. & Chatterjee, N. Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nat. Genet. 50, 1318–1326 (2018).
Google Scholar
Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).
Google Scholar
Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018).
Google Scholar
Mahajan, A. et al. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. Nat. Genet. 54, 560–572 (2022).
Google Scholar
Suzuki, K. et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature 627, 347–357 (2024).
Google Scholar
O’Connor, L. J. et al. Extreme Polygenicity of Complex Traits Is Explained by Negative Selection. Am. J. Hum. Genet. 105, 456–476 (2019).
Google Scholar
Sinnott-Armstrong, N., Naqvi, S., Rivas, M. & Pritchard, J. K. GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background. Elife 10, e58615 (2021).
Google Scholar
Marigorta, U. M. & Gibson, G. A simulation study of gene-by-environment interactions in GWAS implies ample hidden effects. Front. Genet. 5, 225 (2014).
Google Scholar
Nagpal, S., Gibson, G. & Marigorta, U. M. Pervasive Modulation of Obesity Risk by the Environment and Genomic Background. Genes 9, 411 (2018).
Google Scholar
Kulminski, A. M., Loika, Y., Nazarian, A. & Culminskaya, I. Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids. J. Gerontol. A Biol. Sci. Med. Sci. 75, 1811–1819 (2020).
Google Scholar
Wray, N. R., Wijmenga, C., Sullivan, P. F., Yang, J. & Visscher, P. M. Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model. Cell 173, 1573–1580 (2018).
Google Scholar
BasuRay, S., Wang, Y., Smagris, E., Cohen, J. C. & Hobbs, H. H. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc. Natl Acad. Sci. USA 116, 9521–9526 (2019).
Google Scholar
Mahdessian, H. et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc. Natl Acad. Sci. USA 111, 8913–8918 (2014).
Google Scholar
Santoro, N. et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55, 781–789 (2012).
Google Scholar
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