182431-12-5 MBBCVAKAJPKAKM-UHFFFAOYSA-N MBBCVAKAJPKAKM-UHFFFAOYSA-N Lomitapide DTXSID50171294 HP:0001397 HP Hepatic steatosis 1 WIKI increased Lomitapide 2026-09-09T15:38:25 2026-09-09T15:38:25 WikiUser_28 Vertebrates inhbition to MTP Molecular AOPWiki 2026-09-09T15:32:13 2026-09-09T15:32:13 reduced lipid efflux Cellular AOPWiki 2026-09-09T15:33:00 2026-09-09T15:33:00 lipid accumulation Tissue AOPWiki 2026-07-24T11:32:46 2026-07-24T11:32:46 Increase, Liver steatosis Organ <p>Biological state: liver steatosis is the inappropriate storage of fat in hepatocytes.&nbsp;&nbsp;&nbsp;<em>Four major pathways for triglyceride accumulation are: 1. Increased fatty acid uptake; 2. Increased De Novo FA and Lipid Synthesis; 3. Decreased FA Oxidation; 4. Decreased Lipid Efflux (Angrish et al. 2016). &nbsp;Chemical stressors can increase gene expression of key genes involving these pathways, leading to increased accumulation of triglycerides (Aguayo-Orozco et al. 2018). &nbsp;In addition, excessive dietary compounds of fatty compounds can also increase likelihood of accumulation of triglycerides (Nguyen et al. 2008).&nbsp;</em></p> <p>Biological compartment: steatosis is generally an organ-level diagnosis; however, the pathology occurs within the hepatocytes.</p> <p>Role in biology: steatosis is an adverse endpoint.&nbsp;</p> <p><span style="color:#d35400"><strong>Consequences: Liver steatosis, or fatty liver, serves as a pivotal factor in the development of liver fibrosis by triggering a cascade of pathological events. According to the two-strikes hypothesis (Day and James, 1998), liver damage progresses in two stages: the first strike involves the accumulation of lipids in hepatocytes, often due to metabolic disturbances such as insulin resistance, excess free fatty acids, or oxidative stress. This stage, though asymptomatic, increases liver vulnerability by inducing mild oxidative stress and inflammation. The second strike introduces additional insults, such as inflammatory mediators or cellular damage, exacerbating liver injury and promoting fibrogenesis. The accumulation of fat sensitizes the liver to oxidative stress and triggers mechanisms like the activation of hepatic stellate cells (HSCs) and hepatocyte apoptosis or necrosis, central to the fibrotic process. While early-stage steatosis is reversible, chronic steatosis perpetuates a cycle of inflammation and fibrosis, creating a feedback loop that amplifies liver damage (Pafili K et al, 2021). Consequently, liver steatosis is not only a precursor but also a critical driver of fibrosis progression.</strong></span></p> <p><span style="font-size:12px"><span style="color:#d35400"><strong>Day CP, James OF. Steatohepatitis: a tale of two &quot;hits&quot;? Gastroenterology. 1998 Apr;114(4):842-5. doi: 10.1016/s0016-5085(98)70599-2. PMID: 9547102.</strong></span></span></p> <p><span style="font-size:12px"><span style="color:#d35400"><strong>Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab. 2021 Aug;50:101122. doi: 10.1016/j.molmet.2020.101122. Epub 2020 Nov 19. PMID: 33220492; PMCID: PMC8324683.</strong></span></span></p> <p>Description from EU-ToxRisk:</p> <p>Activation of stellate cells results in collagen accumulation and change in extracellular matrix composition in the liver causing fibrosis. (Landesmann, 2016; Koo et al 2016)</p> <p>Steatosis is measured by lipidomics approaches<em> (e.g. Yang and Han 2016)</em> that measure lipid levels, or by histology.&nbsp;&nbsp;<em>Concentrations of triglycerides, cholesterols, fatty acids, and related compounds are measured biochemically&nbsp;include high throughput enzymatic analyses, analytical ultracentrifuging, gradient gel electrophoresis, Nuclear Magnetic Resonance, and other direct assessment techniques (Schaefer et al. 2016).</em></p> <p>Steatosis is the result of perturbations in well-known metabolic pathways that are well-studied and well-known in many taxa.</p> <p><em>Life Stage: The life stage applicable to this key event is all life stages with a liver. &nbsp;Older individuals are more likely to manifest this adverse outcome pathway (adults &gt; juveniles) due to accumulation of triglycerides.</em></p> <p><em>Sex: This key event applies to both males and females.</em></p> <p><em>Taxonomic: This key event appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).</em></p> UBERON:0002107 UBERON liver High Unspecific High All life stages High <p><em>Aguayo-Orozco, A.A., Bois, F.Y., Brunak, S., and Taboureau, O. &nbsp;2018. &nbsp;Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity. &nbsp;Frontiers in Genetics 9(Article 396): 1-15.</em></p> <p><em>Angrish, M.M., Kaiser, J.P., McQueen, C.A., and Chorley, B.N. &nbsp;2016. &nbsp;Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis. &nbsp;Toxicological Sciences 150(2): 261&ndash;268.</em></p> <p>Day CP, James OF. Steatohepatitis: a tale of two &quot;hits&quot;? Gastroenterology. 1998 Apr;114(4):842-5. doi: 10.1016/s0016-5085(98)70599-2. PMID: 9547102.</p> <p>Landesmann, B. (2016). Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis, (2).</p> <p>https://doi.org/10.1016/j.molcel.2005.08.010</p> <p>&nbsp;</p> <p>Koo, J. H., Lee, H. J., Kim, W., &amp; Kim, S. G. (2016). Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2. <em>Gastroenterology</em>, <em>150</em>(1), 181&ndash;193.e8. https://doi.org/10.1053/j.gastro.2015.09.039</p> <p><em>Nguyen, P., Leray, V., Diez, M., Serisier, S., Le Bloc&rsquo;h, J., Siliart, B., and Dumon, H. &nbsp;2008. &nbsp;Liver lipid metabolism. &nbsp;Journal of Animal Physiology and Animal Nutrition 92: 272&ndash;283. &nbsp;</em></p> <p><em>Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab. 2021 Aug;50:101122. doi: 10.1016/j.molmet.2020.101122. Epub 2020 Nov 19. PMID: 33220492; PMCID: PMC8324683.</em></p> <p><em>Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki, E., Thai, N., and Astalos, B. The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. [Updated 2016 Mar 29]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355892/</em></p> <p><em>Yang, K. and Han, X. &nbsp;2016. &nbsp;Lipidomics: Techniques, applications, and outcomes related to biomedical sciences. &nbsp;Trends in Biochemical Sciences 2016 November ; 41(11): 954&ndash;969.</em></p> <p><em>NOTE: Italics symbolize edits from John Frisch</em></p> AOPWiki 2016-11-29T18:41:24 2026-02-11T05:41:52 small intestine steatosis Organ AOPWiki 2026-09-09T15:34:58 2026-09-09T15:34:58 AOPWiki 2026-09-09T15:35:21 2026-09-09T15:35:21 AOPWiki 2026-09-09T15:35:38 2026-09-09T15:35:38 AOPWiki 2026-09-09T15:35:55 2026-09-09T15:35:55 AOPWiki 2026-09-09T15:36:09 2026-09-09T15:36:09 Inhibition to Microsomal Triglyceride Transfer Protein Leads to Steatosis Huan Yang <p>Huan Yang</p> All rights reserved 2.8 <p><span style="font-size:11pt"><span style="font-family:Cambria,serif">This document outlines the development of an AOP linking the MIE of inhibition to Microsomal Triglyceride Transfer Protein (MTP) to (multiorgan) steatosis. The AOP maps the molecular initiating event (MTP inhibition) to the primary key event of reduced lipid efflux. This disruption branches into tissue-specific lipid accumulation in the liver and small intestine, ultimately resulting in hepatic and intestinal steatosis.</span></span></p> <p>Steatosis is a regulatory endpoint and has been used as an endpoint in many US EPA assessments, including IRIS assessments.</p> adjacent Moderate High adjacent High High adjacent Moderate Moderate adjacent Not Specified Not Specified Moderate Mixed Moderate Adults <div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td>sex</td> <td>&nbsp;</td> <td>&nbsp;</td> </tr> </tbody> </table> </div> Not Specified AOPWiki 2026-09-09T15:28:48 2026-09-09T15:40:46