{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:21:45Z","timestamp":1790392905093,"version":"4.1.0"},"reference-count":101,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,9]],"date-time":"2019-07-09T00:00:00Z","timestamp":1562630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K99\/R00ES024455"],"award-info":[{"award-number":["K99\/R00ES024455"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Microcystin-LR (MCLR) is a hepatotoxic cyanotoxin reported to cause a phenotype similar to nonalcoholic steatohepatitis (NASH). NASH is a common progressive liver disease that advances in severity due to exogenous stressors such as poor diet and toxicant exposure. Our objective was to determine how sub-chronic MCLR toxicity affects preexisting diet-induced NASH. Sprague-Dawley rats were fed one of three diets for 10 weeks: control, methionine and choline deficient (MCD), or high fat\/high cholesterol (HFHC). After six weeks of diet, animals received vehicle, 10 \u00b5g\/kg, or 30 \u00b5g\/kg MCLR via intraperitoneal injection every other day for the final 4 weeks. Incidence and severity scoring of histopathology endpoints suggested that MCLR toxicity drove NASH to a less fatty and more fibrotic state. In general, expression of genes involved in de novo lipogenesis and fatty acid esterification were altered in favor of decreased steatosis. The higher MCLR dose increased expression of genes involved in fibrosis and inflammation in the control and HFHC groups. These data suggest MCLR toxicity in the context of preexisting NASH may drive the liver to a more severe phenotype that resembles burnt-out NASH.<\/jats:p>","DOI":"10.3390\/toxins11070398","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T03:05:26Z","timestamp":1562727926000},"page":"398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Sub-Chronic Microcystin-LR Liver Toxicity in Preexisting Diet-Induced Nonalcoholic Steatohepatitis in Rats"],"prefix":"10.3390","volume":"11","author":[{"given":"Tarana","family":"Arman","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine D.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Montonye","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Goedken","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3835-7761","authenticated-orcid":false,"given":"John D.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.watres.2011.11.021","article-title":"Global warming and hepatotoxin production by cyanobacteria: What can we learn from experiments?","volume":"46","author":"Gorokhova","year":"2012","journal-title":"Water Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bui, T., Dao, T.-S., Vo, T.-G., and L\u00fcrling, M. (2018). Warming Affects Growth Rates and Microcystin Production in Tropical Bloom-Forming Microcystis Strains. Toxins, 10.","DOI":"10.3390\/toxins10030123"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1046\/j.1365-2761.2001.00273.x","article-title":"Confirmation of catfish, Ictalurus punctatus (Rafinesque), mortality from Microcystis toxins","volume":"24","author":"Zimba","year":"2001","journal-title":"J. Fish Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ecoenv.2004.04.006","article-title":"Microcystin-producing blooms-a serious global public health issue","volume":"59","author":"Azeiteiro","year":"2004","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.envint.2013.06.013","article-title":"State of knowledge and concerns on cyanobacterial blooms and cyanotoxins","volume":"59","author":"Merel","year":"2013","journal-title":"Environ. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.aquaculture.2008.05.007","article-title":"A review of cyanobacterial odorous and bioactive metabolites: Impacts and management alternatives in aquaculture","volume":"280","author":"Smith","year":"2008","journal-title":"Aquaculture"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1365-2761.1994.tb00211.x","article-title":"Cyanobacterial (blue-green algal) bloom associated pathology in brown trout, Salmo trutta L., in Loch Leven, Scotland","volume":"17","author":"Rodger","year":"1994","journal-title":"J. Fish Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5806","DOI":"10.1021\/es200285c","article-title":"Evaluating microcystin exposure risk through fish consumption","volume":"45","author":"Poste","year":"2011","journal-title":"Environ. Sci. Technol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.toxicon.2006.07.009","article-title":"Foodweb transfer, accumulation, and depuration of microcystins, a cyanobacterial toxin, in pumpkinseed sunfish (Lepomis gibbosus)","volume":"48","author":"Smith","year":"2006","journal-title":"Toxicon"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.toxicon.2013.09.008","article-title":"Spatial and thematic distribution of research on cyanotoxins","volume":"76","author":"Merel","year":"2013","journal-title":"Toxicon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1177\/096032719901800305","article-title":"The toxicity of cyanobacterial toxins in the mouse: I Microcystin-LR","volume":"18","author":"Fawell","year":"1999","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/toxsci\/kfp009","article-title":"First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage","volume":"108","author":"Chen","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1002\/hep.29310","article-title":"Serum microcystin levels positively linked with risk of hepatocellular carcinoma: A case-control study in southwest China","volume":"66","author":"Zheng","year":"2017","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1093\/carcin\/17.6.1317","article-title":"Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay","volume":"17","author":"Ueno","year":"1996","journal-title":"Carcinogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1080\/10590500802668016","article-title":"Freshwater cyanobacterial blooms and primary liver cancer epidemiological studies in Serbia","volume":"27","year":"2009","journal-title":"J. Environ. Sci. Health Part C"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1568-9883(02)00026-4","article-title":"Blue green algal (cyanobacterial) toxins, surface drinking water, and liver cancer in Florida","volume":"1","author":"Fleming","year":"2002","journal-title":"Harmful Algae"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.3748\/wjg.v21.i14.4103","article-title":"Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: An open question","volume":"21","author":"Streba","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.4254\/wjh.v7.i11.1450","article-title":"Non-alcoholic fatty liver disease in 2015","volume":"7","author":"Ahmed","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1002\/hep.26072","article-title":"Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause?","volume":"57","author":"Samer","year":"2013","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1289\/ehp.1002720","article-title":"Polychlorinated biphenyls, lead, and mercury are associated with liver disease in american adults: NHANES 2003\u20132004","volume":"118","author":"Cave","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1016\/j.jnutbio.2013.01.009","article-title":"Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6\/J mice","volume":"24","author":"Wahlang","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/toxsci\/kft104","article-title":"Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice","volume":"134","author":"Seth","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1093\/toxsci\/kfx120","article-title":"Nonalcoholic fatty liver disease is a susceptibility factor for perchloroethylene-induced liver effects in mice","volume":"159","author":"Cichocki","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.taap.2014.06.019","article-title":"Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease","volume":"279","author":"Wahlang","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1177\/0192623314549960","article-title":"Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents","volume":"43","author":"Wahlang","year":"2015","journal-title":"Toxicol. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.taap.2016.09.026","article-title":"Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice","volume":"311","author":"Anders","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12940-015-0026-7","article-title":"Cyanobacteria blooms and non-alcoholic liver disease: Evidence from a county level ecological study in the United States","volume":"14","author":"Zhang","year":"2015","journal-title":"Environ. Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1021\/acs.est.5b03369","article-title":"First Identification of the Toxicity of Microcystins on Pancreatic Islet Function in Humans and the Involved Potential Biomarkers","volume":"50","author":"Zhao","year":"2016","journal-title":"Environ. Sci. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00204-016-1681-3","article-title":"Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: A systems toxicology study","volume":"91","author":"He","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrgastro.2010.191","article-title":"Animal models of nonalcoholic fatty liver disease","volume":"8","author":"Hebbard","year":"2011","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.lfs.2006.03.021","article-title":"High-fat emulsion-induced rat model of nonalcoholic steatohepatitis","volume":"79","author":"Zou","year":"2006","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1007\/s10620-015-3977-1","article-title":"Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame","volume":"61","author":"Ibrahim","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.toxicon.2007.11.012","article-title":"Hepatic recovery after damage produced by sub-chronic intoxication with the cyanotoxin microcystin LR","volume":"51","author":"Andrinolo","year":"2008","journal-title":"Toxicon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.toxicon.2009.08.008","article-title":"Alteration and recovery of the antioxidant system induced by sub-chronic exposure to microcystin-LR in mice: Its relation to liver lipid composition","volume":"55","author":"Sedan","year":"2010","journal-title":"Toxicon"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.toxicon.2013.03.002","article-title":"Biomarkers of prolonged exposure to microcystin-LR in mice","volume":"68","author":"Sedan","year":"2013","journal-title":"Toxicon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1021\/es201514h","article-title":"Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice","volume":"46","author":"Zhao","year":"2012","journal-title":"Environ. Sci. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1080\/01926230701383210","article-title":"Hepatic gene expression changes in mice associated with prolonged sublethal microcystin exposure","volume":"35","author":"Clark","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1177\/019262339902700512","article-title":"Hepatic Oxidative Stress Following Prolonged Sublethal Microcystin LR Exposure","volume":"27","author":"Guzman","year":"1999","journal-title":"Toxicol. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1124\/dmd.113.055996","article-title":"Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models","volume":"42","author":"Canet","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"846","DOI":"10.4254\/wjh.v7.i6.846","article-title":"Non-alcoholic fatty liver disease: The diagnosis and management","volume":"7","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.aquaculture.2008.05.015","article-title":"Ultrastructural alteration of lymphocytes in spleen and pronephros of grass carp (Ctenopharyngodon idella) experimentally exposed to microcystin-LR","volume":"280","author":"Wei","year":"2008","journal-title":"Aquaculture"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0378-4274(01)00339-3","article-title":"Microcystin-induced down-regulation of lymphocyte functions through reduced IL-2 mRNA stability","volume":"122","author":"Yea","year":"2001","journal-title":"Toxicol. Lett."},{"key":"ref_44","first-page":"144","article-title":"Role of spleen enlargement in cirrhosis with portal hypertension","volume":"34","author":"Sacerdoti","year":"2003","journal-title":"Dig. Liver Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1007\/s11695-010-0181-4","article-title":"Pro-and anti-inflammatory cytokines in Steatosis and steatohepatitis","volume":"20","author":"Rabelo","year":"2010","journal-title":"Obes. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/path.4829","article-title":"Animal models of non-alcoholic fatty liver disease: Current perspectives and recent advances","volume":"241","author":"Lau","year":"2017","journal-title":"J. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1177\/0192623312468517","article-title":"Toxicant-associated Steatohepatitis","volume":"41","author":"Wahlang","year":"2013","journal-title":"Toxicol. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1007\/s00535-016-1298-6","article-title":"Upregulated absorption of dietary palmitic acids with changes in intestinal transporters in non-alcoholic steatohepatitis (NASH)","volume":"52","author":"Utsunomiya","year":"2017","journal-title":"J. Gastroenterol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.metabol.2016.01.001","article-title":"Non-alcoholic fatty liver disease and diabetes","volume":"65","author":"Hazlehurst","year":"2016","journal-title":"Metabolism"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jhazmat.2016.04.019","article-title":"Microcystin-LR induces dysfunction of insulin secretion in rat insulinoma (INS-1) cells: Implications for diabetes mellitus","volume":"314","author":"Zhao","year":"2016","journal-title":"J. Hazard. Mater."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0140-6736(97)12285-1","article-title":"Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil","volume":"352","author":"Pouria","year":"1998","journal-title":"Lancet"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.envpol.2017.01.061","article-title":"Impairment of endoplasmic reticulum is involved in B-cell dysfunction induced by microcystin-LR","volume":"223","author":"Zhao","year":"2017","journal-title":"Environ. Pollut."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.tem.2015.11.008","article-title":"The Role of Cholesterol in the Pathogenesis of NASH","volume":"27","author":"Ioannou","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kim, E.J., Kim, B., Seo, H.S., Lee, Y.J., Kim, H.H., Son, H.-H., and Choi, M.H. (2014). Cholesterol-induced non-alcoholic fatty liver disease and atherosclerosis aggravated by systemic inflammation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097841"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/tox.22456","article-title":"Microcystin-LR disrupts insulin signaling by hyperphosphorylating insulin receptor substrate 1 and glycogen synthase","volume":"33","author":"Li","year":"2017","journal-title":"Environ. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.taap.2004.08.012","article-title":"Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin","volume":"203","author":"Fischer","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/toxsci\/kfm054","article-title":"Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3","volume":"97","author":"Komatsu","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Niedermeyer, T.H.J., Daily, A., Swiatecka-Hagenbruch, M., and Moscow, J.A. (2014). Selectivity and Potency of Microcystin Congeners against OATP1B1 and OATP1B3 Expressing Cancer Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091476"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.toxicon.2009.11.019","article-title":"Abrogation of microcystin cytotoxicity by MAP kinase inhibitors and N-acetyl cysteine is confounded by OATPIB1 uptake activity inhibition","volume":"55","author":"Daily","year":"2010","journal-title":"Toxicon"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1093\/toxsci\/kfn038","article-title":"Characterization of organic anion transporting polypeptide 1b2-null mice: Essential role in hepatic uptake\/toxicity of phalloidin and microcystin-LR","volume":"103","author":"Lu","year":"2008","journal-title":"Toxicol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1002\/cpt.66","article-title":"Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis","volume":"97","author":"Ferslew","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.pharmthera.2015.03.005","article-title":"Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability","volume":"151","author":"Clarke","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1124\/jpet.113.211284","article-title":"Experimental Nonalcoholic Steatohepatitis Increases Exposure to Simvastatin Hydroxy Acid by Decreasing Hepatic Organic Anion Transporting Polypeptide Expression","volume":"348","author":"Clarke","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jhep.2014.02.021","article-title":"Synergistic interaction between genetics and disease on pravastatin disposition","volume":"61","author":"Clarke","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.cell.2006.09.025","article-title":"Structure of Protein Phosphatase 2A Core Enzyme Bound to Tumor-Inducing Toxins","volume":"127","author":"Xing","year":"2006","journal-title":"Cell"},{"key":"ref_66","first-page":"G224","article-title":"Protein phosphatase inhibition and in vivo hepatotoxicity of microcystins","volume":"265","author":"Runnegar","year":"2017","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.4161\/15384101.2014.965068","article-title":"The role of cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling","volume":"13","author":"Xu","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"740","DOI":"10.7150\/ijbs.7.740","article-title":"Microcystin-LR (MCLR) induces a compensation of PP2A activity mediated by \u03b14 protein in HEK293 cells","volume":"7","author":"Li","year":"2011","journal-title":"Int. J. Biol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0014-5793(94)00382-3","article-title":"Identification of protein phosphatase 2A as the primary target for microcystin-LR in rat liver homogenates","volume":"344","author":"Toivola","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1007\/s00018-018-2860-6","article-title":"Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease","volume":"75","author":"Ipsen","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.2337\/db14-0369","article-title":"Free fatty acid uptake in humans with CD36 deficiency","volume":"63","author":"Hames","year":"2014","journal-title":"Diabetes"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.jhep.2018.04.006","article-title":"CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis","volume":"69","author":"Zhao","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1146\/annurev-nutr-071812-161220","article-title":"Structure-Function of CD36 and Importance of Fatty Acid Signal Transduction in Fat Metabolism","volume":"34","author":"Pepino","year":"2014","journal-title":"Annu. Rev. Nutr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3809","DOI":"10.1007\/s00018-016-2331-x","article-title":"Is hepatic lipogenesis fundamental for NAFLD\/NASH? A focus on the nuclear receptor coactivator PGC-1\u03b2","volume":"73","author":"Ducheix","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1074\/jbc.M807616200","article-title":"Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: Role of stearoyl-Coa desaturase","volume":"284","author":"Li","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1002\/hep.30097","article-title":"Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents","volume":"68","author":"Goedeke","year":"2018","journal-title":"Hepatology"},{"key":"ref_77","first-page":"221","article-title":"CEG-62831-molecular-pathways-in-non-alcoholic-fatty-liver-disease","volume":"7","author":"Berlanga","year":"2014","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1507\/endocrj.K07E-110","article-title":"ChREBP: A Glucose-activated Transcription Factor Involved in the Development of Metabolic Syndrome","volume":"55","author":"Iizuka","year":"2008","journal-title":"Endocr. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.nutr.27.061406.093618","article-title":"ChREBP, a Transcriptional Regulator of Glucose and Lipid Metabolism","volume":"27","author":"Postic","year":"2007","journal-title":"Annu. Rev. Nutr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3350\/cmh.2013.19.3.210","article-title":"Nonalcoholic fatty liver disease: Molecular mechanisms for the hepatic steatosis","volume":"19","author":"Koo","year":"2013","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/MPG.0b013e31822578db","article-title":"Mechanisms of lipotoxicity in NAFLD and clinical implications","volume":"53","author":"Ibrahim","year":"2011","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.bbalip.2008.10.010","article-title":"Glycerol-3-phosphate acyltransferases: Rate limiting enzymes of triacylglycerol biosynthesis","volume":"1791","author":"Wendel","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/hep.21655","article-title":"Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis","volume":"45","author":"Yamaguchi","year":"2007","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cmet.2005.06.006","article-title":"Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice","volume":"2","author":"Neschen","year":"2005","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Dai, D., Wen, F., Zhou, S., Su, Z., Liu, G., Wang, M., Zhou, J., and He, F. (2017). Association of MTTP gene variants with pediatric NAFLD: A candidate-gene-based analysis of single nucleotide variations in obese children. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185396"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.jhep.2011.01.048","article-title":"Lack of interleukin-1\u03b1 or interleukin-1\u03b2 inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice","volume":"55","author":"Kamari","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/toxsci\/kft180","article-title":"Microcystin-LR Exhibits Immunomodulatory Role in Mouse Primary Hepatocytes Through Activation of the NF-\u03baB and MAPK Signaling Pathways","volume":"136","author":"Zhang","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxicon.2019.03.002","article-title":"Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity","volume":"162","author":"Clarke","year":"2019","journal-title":"Toxicon"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1053\/j.gastro.2016.06.022","article-title":"Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol","volume":"151","author":"Rahman","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.0901-9928.2000.870108.x","article-title":"Supernatants from macrophages stimulated with microcystin-LR induce electrogenic intestinal response in rabbit ileum","volume":"87","author":"Rocha","year":"2000","journal-title":"Pharmacol. Toxicol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"R103","DOI":"10.1007\/s004240000023","article-title":"Subchronic liver injuries caused by microcystins","volume":"440","author":"Frangez","year":"2000","journal-title":"Pfl\u00fcgers Arch. Eur. J. Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.jhep.2004.09.012","article-title":"The histological course of nonalcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies","volume":"42","author":"Adams","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1522-7278(199902)14:1<57::AID-TOX9>3.0.CO;2-J","article-title":"Toxicity of the cyanobacterial toxin microcystin-LR to rats after 28 days intake with the drinking water","volume":"14","author":"Heinze","year":"1999","journal-title":"Environ. Toxicol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0041-0101(96)00129-8","article-title":"Hepatic necrosis in aged mice by oral administration of microcystin-LR","volume":"35","author":"Ito","year":"1997","journal-title":"Toxicon"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1002\/hep.23594","article-title":"Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection","volume":"51","author":"Starley","year":"2010","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.cgh.2011.04.007","article-title":"Patients With NASH and Cryptogenic Cirrhosis Are Less Likely Than Those With Hepatitis C to Receive Liver Transplants","volume":"9","author":"Landaverde","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Machado, M.V., Michelotti, G.A., Xie, G., De Almeida, T.P., Boursier, J., Bohnic, B., Guy, C.D., and Diehl, A.M. (2015). Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132315"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1194\/jlr.M800042-JLR200","article-title":"Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet","volume":"49","author":"Rinella","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1038\/labinvest.2010.112","article-title":"Attenuated progression of diet-induced steatohepatitis in glutathione-deficient mice","volume":"90","author":"Haque","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jneumeth.2008.05.003","article-title":"Total protein STAIN","volume":"172","author":"Aldridge","year":"2009","journal-title":"J. Neurosci. Methods"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/11\/7\/398\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:03:45Z","timestamp":1760187825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/11\/7\/398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,9]]},"references-count":101,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["toxins11070398"],"URL":"https:\/\/doi.org\/10.3390\/toxins11070398","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,9]]}}}