{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T17:44:31Z","timestamp":1789839871599,"version":"4.0.1"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health of the Czech Republic under its conceptual development of research organisations programme","award":["IKEM, IN 00023001"],"award-info":[{"award-number":["IKEM, IN 00023001"]}]},{"name":"Ministry of Health of the Czech Republic","award":["NU20-01-00083"],"award-info":[{"award-number":["NU20-01-00083"]}]},{"name":"Ministry of Health of the Czech Republic","award":["IGA_LF_2021_013."],"award-info":[{"award-number":["IGA_LF_2021_013."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p \u02c2 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p \u02c2 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p \u02c2 0.05) and decreased CYP4A (p \u02c2 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p \u02c2 0.01), lipogenesis (p \u02c2 0.05) and lipolysis (p \u02c2 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.<\/jats:p>","DOI":"10.3390\/ijms22094527","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T02:31:43Z","timestamp":1619490703000},"page":"4527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9076-3399","authenticated-orcid":false,"given":"Hana","family":"Malinsk\u00e1","sequence":"first","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"H\u00fcttl","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Mikl\u00e1nkov\u00e1","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslava","family":"Trnovsk\u00e1","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-8848","authenticated-orcid":false,"given":"Iveta","family":"Zapletalov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-4971","authenticated-orcid":false,"given":"Martin","family":"Poruba","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4331-7636","authenticated-orcid":false,"given":"Irena","family":"Markov\u00e1","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ygyno.2008.02.025","article-title":"Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: A controlled, population-based study (HUNT-2)","volume":"109","author":"Dorum","year":"2008","journal-title":"Gynecol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/sj.ijo.0803240","article-title":"Insulin resistance, obesity, and metabolic syndrome among non-diabetic pre- and post-menopausal women in North Taiwan","volume":"30","author":"Lin","year":"2006","journal-title":"Int. J. Obes."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"567945","DOI":"10.1155\/2015\/567945","article-title":"Similar and additive effects of ovariectomy and diabetes on insulin resistance and lipid metabolism","volume":"2015","author":"Tawfik","year":"2015","journal-title":"Biochem. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1515\/hmbci-2014-0007","article-title":"Estradiol regulates insulin signaling and inflammation in adipose tissue","volume":"17","author":"Shen","year":"2014","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1210\/en.2013-1385","article-title":"A change in liver metabolism but not in brown adipose tissue thermogenesis is an early event in ovariectomy-induced obesity in rats","volume":"155","author":"Nigro","year":"2014","journal-title":"Endocrinology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1097\/MOL.0000000000000296","article-title":"Relevance of lipid metabolism for brown fat visualization and quantification","volume":"27","author":"Schilperoort","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.pcad.2018.07.002","article-title":"Role of Human Brown Fat in Obesity, Metabolism and Cardiovascular Disease: Strategies to Turn Up the Heat","volume":"61","author":"Ruiz","year":"2018","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.mce.2015.05.025","article-title":"Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans","volume":"418 Pt 2","author":"Lee","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"bqaa134","DOI":"10.1210\/endocr\/bqaa134","article-title":"NAFLD and NASH in Postmenopausal Women: Implications for Diagnosis and Treatment","volume":"161","author":"DiStefano","year":"2020","journal-title":"Endocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0306-3623(96)00246-7","article-title":"The cytochrome P450 4 (CYP4) family","volume":"28","author":"Simpson","year":"1997","journal-title":"Gen. Pharm."},{"key":"ref_11","first-page":"1121","article-title":"CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROSinduced lipid peroxidation and inflammation","volume":"45","author":"Gao","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-7075-10-32","article-title":"Fructose-induced stress signaling in the liver involves methylglyoxal","volume":"10","author":"Wei","year":"2013","journal-title":"Nutr. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/ncpendmet0616","article-title":"The metabolic syndrome in women","volume":"3","author":"Koruda","year":"2007","journal-title":"Nat. Clin. Pr. Endocrinol. Metab."},{"key":"ref_14","first-page":"5","article-title":"Animal Models for the Study of the Relationships between Diet and Obesity: A Focus on Dietary Protein and Estrogen Deficiency","volume":"4","author":"Blachier","year":"2017","journal-title":"Front. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.brainres.2010.04.056","article-title":"Metabolic impact of sex hormones on obesity","volume":"1350","author":"Brown","year":"2010","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Maliszewska, K., and Kretowski, A. (2021). Brown Adipose Tissue and Its Role in Insulin and Glucose Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041530"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1097\/MOL.0000000000000504","article-title":"Brown adipose tissue and lipid metabolism","volume":"29","author":"Heeren","year":"2018","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1530\/JME-20-0210","article-title":"Sex difference in the mouse BAT transcriptome reveals a role of progesterone","volume":"66","author":"Kaikaew","year":"2021","journal-title":"J. Mol. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JME-12-0043","article-title":"Role of sex hormones in modulation of brown adipose tissue activity","volume":"49","author":"Quarta","year":"2012","journal-title":"J. Mol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/978-3-319-70178-3_15","article-title":"Estradiol Regulation of Brown Adipose Tissue Thermogenesis","volume":"1043","author":"Lopez","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.cmet.2011.06.012","article-title":"Different metabolic responses of human brown adipose tissue to activation by cold and insulin","volume":"14","author":"Orava","year":"2011","journal-title":"Cell. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1258\/mi.2010.010028","article-title":"Effects of ovariectomy and estrogen replacement therapy on visceral adipose tissue and serum adiponectin levels in rats","volume":"16","author":"Babaei","year":"2010","journal-title":"Menopause Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/sj.ijo.0803427","article-title":"Sex-specific determinants of serum adiponectin in older adults: The role of endogenous sex hormones","volume":"31","author":"Laughlin","year":"2007","journal-title":"Int. J. Obes."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jo, D., Son, Y., Yoon, G., Song, J., and Kim, O.Y. (2020). Role of Adiponectin and Brain Derived Neurotrophic Factor in Metabolic Regulation Involved in Adiposity and Body Fat Browning. J. Clin. Med., 10.","DOI":"10.3390\/jcm10010056"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1538\/expanim.16-0087","article-title":"Effects of 17beta-estradiol on leptin signaling in anterior pituitary of ovariectomized rats","volume":"66","author":"Yin","year":"2017","journal-title":"Exp. Anim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.cca.2015.02.040","article-title":"Relationship between serum leptin levels and bone mineral density: A systematic review and meta-analysis","volume":"444","author":"Liu","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1530\/JOE-19-0321","article-title":"Effects of ERbeta and ERalpha on OVX-induced changes in adiposity and insulin resistance","volume":"245","author":"Zidon","year":"2020","journal-title":"J. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9597","DOI":"10.1073\/pnas.1409229111","article-title":"Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans","volume":"111","author":"Szendroedi","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JOE-16-0513","article-title":"Hepatic lipid accumulation: Cause and consequence of dysregulated glucoregulatory hormones","volume":"234","author":"Geisler","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.nutres.2015.09.013","article-title":"Prevention of hyperphagia prevents ovariectomy-induced triacylglycerol accumulation in liver, but not plasma","volume":"35","author":"Kitson","year":"2015","journal-title":"Nutr. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s11010-020-03879-4","article-title":"Ovariectomized rodents as a menopausal metabolic syndrome model. A minireview","volume":"475","year":"2020","journal-title":"Mol. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1194\/jlr.R084244","article-title":"ABCG5 and ABCG8: More than a defense against xenosterols","volume":"59","author":"Patel","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.33549\/physiolres.934322","article-title":"The effect of combined diet containing n-3 polyunsaturated fatty acids and silymarin on metabolic syndrome in rats","volume":"68","author":"Poruba","year":"2019","journal-title":"Physiol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.tibs.2018.01.005","article-title":"SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond","volume":"43","author":"Ye","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1055\/s-0034-1370910","article-title":"LDL receptor and Pcsk9 transcripts are decreased in liver of ovariectomized rats: Effects of exercise training","volume":"46","author":"Chapados","year":"2014","journal-title":"Horm. Metab. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.bbalip.2014.07.002","article-title":"Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis","volume":"1842","author":"Soffientini","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/978-3-319-70178-3_12","article-title":"Role of Estrogens in the Regulation of Liver Lipid Metabolism","volume":"1043","author":"Palmisano","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.3109\/00498254.2013.797622","article-title":"Hormonal regulation of Cyp4a isoforms in mouse liver and kidney","volume":"43","author":"Zhang","year":"2013","journal-title":"Xenobiotica"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1006\/bbrc.1999.0202","article-title":"Altered expression of hepatic CYP2E1 and CYP4A in obese, diabetic ob\/ob mice, and fa\/fa Zucker rats","volume":"255","author":"Enriquez","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1172\/JCI8814","article-title":"CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis","volume":"105","author":"Leclercq","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1073\/pnas.1700172114","article-title":"Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis","volume":"114","author":"Zhang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jamwal, R., and Barlock, B.J. (2020). Nonalcoholic Fatty Liver Disease (NAFLD) and Hepatic Cytochrome P450 (CYP) Enzymes. Pharmaceuticals, 13.","DOI":"10.3390\/ph13090222"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Huttl, M., Markova, I., Miklankova, D., Makovicky, P., Pelikanova, T., Seda, O., Sedova, L., and Malinska, H. (2020). Adverse Effects of Methylglyoxal on Transcriptome and Metabolic Changes in Visceral Adipose Tissue in a Prediabetic Rat Model. Antioxidants, 9.","DOI":"10.3390\/antiox9090803"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6362910","DOI":"10.1155\/2019\/6362910","article-title":"Dietary Glycotoxins Impair Hepatic Lipidemic Profile in Diet-Induced Obese Rats Causing Hepatic Oxidative Stress and Insulin Resistance","volume":"2019","author":"Neves","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1007\/s12020-012-9795-8","article-title":"Methylglyoxal, obesity, and diabetes","volume":"43","author":"Matafome","year":"2013","journal-title":"Endocrine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.nut.2015.03.011","article-title":"Conjugated linoleic acid reduces visceral and ectopic lipid accumulation and insulin resistance in chronic severe hypertriacylglycerolemia","volume":"31","author":"Malinska","year":"2015","journal-title":"Nutrition"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"681","DOI":"10.33549\/physiolres.930380","article-title":"Transgenic expression of CD36 in the spontaneously hypertensive rat is associated with amelioration of metabolic disturbances but has no effect on hypertension","volume":"52","author":"Pravenec","year":"2003","journal-title":"Physiol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1042\/bj3440109","article-title":"Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose","volume":"344 Pt 1","author":"Thornalley","year":"1999","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1042\/BST20140010","article-title":"Measurement of glyoxalase activities","volume":"42","author":"Arai","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fphar.2019.00056","article-title":"Fenofibrate Decreases Hepatic P-Glycoprotein in a Rat Model of Hereditary Hypertriglyceridemia","volume":"10","author":"Poruba","year":"2019","journal-title":"Front. Pharm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4527\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:53:04Z","timestamp":1760161984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,26]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094527"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094527","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,26]]}}}