{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:57:59Z","timestamp":1790657879119,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Grant-in-Aid for Scientific Research (B) (Grant Number 19H02916)"],"award-info":[{"award-number":["Grant-in-Aid for Scientific Research (B) (Grant Number 19H02916)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Grant-in-Aid for Scientific Research (B) (Grant Number 19H02916)"],"award-info":[{"award-number":["Grant-in-Aid for Scientific Research (B) (Grant Number 19H02916)"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: The very low-density lipoprotein receptor (VLDLR) mediates VLDL uptake in peripheral tissues. This study investigated sex differences in hepatic VLDLR response to protein restriction and its relationship with hepatic lipid accumulation. Methods: Male and female wild-type (WT) and Vldlr knockout (KO) mice were fed control (20% protein) or low-protein (2% protein) diets for 20 days. Hepatic VLDLR expression and triglyceride levels were determined, followed by RNA sequencing and Gene Ontology (GO) analysis. Results: Hepatic Vldlr mRNA and protein levels were higher in females than in males. Protein restriction induced 9-fold and 2.5-fold increases in Vldlr mRNA and VLDLR protein, respectively, in males, whereas females showed only a 1.6-fold increase in VLDLR protein without significant Vldlr mRNA induction. The ATF4 target genes Asns and Fgf21 responded similarly to protein restriction in both sexes. Although females had higher hepatic triglyceride levels than males, this difference persisted in Vldlr KO mice. RNA sequencing revealed sex-dependent effects of Vldlr knockout on hepatic gene expression, with inflammation- and immune-related terms predominantly identified in females. Conclusions: Sex differences in hepatic VLDLR expression do not account for sex differences in hepatic lipid accumulation. The sex-dependent VLDLR response to protein restriction may involve mechanisms other than differential ATF4 activation. Vldlr deficiency was associated with sex-dependent hepatic gene expression changes, particularly those involved in inflammation- and immune-related functions in females. These findings suggest that hepatic VLDLR may have functions beyond its established role in lipoprotein uptake and lipid metabolism and may be relevant to sex-dependent hepatic responses to low-protein nutrition.<\/jats:p>","DOI":"10.3390\/nu18193153","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:53Z","timestamp":1790267393000},"page":"3153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex Differences in Hepatic VLDLR Response to Protein Restriction and Its Relationship with Hepatic Lipid Accumulation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0885-9918","authenticated-orcid":false,"given":"Jiuxiang","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4125-7019","authenticated-orcid":false,"given":"Asako","family":"Takenaka","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","first-page":"19","article-title":"Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis","volume":"85","author":"Go","year":"2012","journal-title":"Yale J. Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1074\/jbc.M109966200","article-title":"Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency","volume":"277","author":"Yagyu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/oxfordjournals.jbchem.a022175","article-title":"Expression and characterization of a very low density lipoprotein receptor variant lacking the O-linked sugar region generated by alternative splicing","volume":"124","author":"Iijima","year":"1998","journal-title":"J. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1128\/MCB.00235-16","article-title":"Functional differences of very-low-density lipoprotein receptor splice variants in regulating Wnt signaling","volume":"36","author":"Chen","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0021-9150(99)00068-4","article-title":"Mouse very low-density lipoprotein receptor (VLDLR): Gene structure, tissue-specific expression and dietary and developmental regulation","volume":"145","author":"Tiebel","year":"1999","journal-title":"Atherosclerosis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1016\/j.bcp.2011.09.003","article-title":"Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists","volume":"82","author":"Tao","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1172\/JCI43068","article-title":"The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction","volume":"121","author":"Perman","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1194\/jlr.M400009-JLR200","article-title":"The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis","volume":"45","author":"Goudriaan","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8453","DOI":"10.1073\/pnas.92.18.8453","article-title":"Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor","volume":"92","author":"Frykman","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"200","DOI":"10.5551\/jat.11.200","article-title":"The very low-density lipoprotein (VLDL) receptor: Characterization and functions as a peripheral lipoprotein receptor","volume":"11","author":"Takahashi","year":"2004","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/hep.26126","article-title":"Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor","volume":"57","author":"Jo","year":"2013","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1002\/hep.26912","article-title":"Nuclear factor (erythroid-derived 2)-like 2 activation-induced hepatic very-low-density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice","volume":"59","author":"Wang","year":"2014","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.molmet.2017.12.008","article-title":"Hepatic regulation of VLDL receptor by PPAR\u03b2\/\u03b4 and FGF21 modulates non-alcoholic fatty liver disease","volume":"8","author":"Zarei","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101685","DOI":"10.1016\/j.molmet.2023.101685","article-title":"VLDL receptor gene therapy for reducing atherogenic lipoproteins","volume":"69","author":"Krauss","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8422","DOI":"10.1038\/s41467-024-52751-2","article-title":"A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated re-uptake","volume":"15","author":"Martini","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/s41467-017-01232-w","article-title":"Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation","volume":"8","author":"Shin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1074\/jbc.M113.515320","article-title":"Very low density lipoprotein receptor (VLDLR) expression is a determinant factor in adipose tissue inflammation and adipocyte-macrophage interaction","volume":"289","author":"Nguyen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1182\/blood-2011-09-382580","article-title":"Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes","volume":"119","author":"Yakovlev","year":"2012","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1055\/s-0039-1695008","article-title":"Fibrin-VLDL receptor-dependent pathway promotes leukocyte transmigration by inhibiting Src kinase Fyn and is a target for fibrin \u03b215-42 peptide","volume":"119","author":"Yakovlev","year":"2019","journal-title":"Thromb. Haemost."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8003","DOI":"10.1038\/s41598-021-87568-2","article-title":"Very low-density lipoprotein receptor increases in a liver-specific manner due to protein deficiency but does not affect fatty liver in mice","volume":"11","author":"Oshio","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/09168451.2014.877825","article-title":"Insulin injection restored increased insulin receptor substrate (IRS)-2 protein during short-term protein restriction but did not affect reduced insulin-like growth factor (IGF)-I mRNA or increased triglyceride accumulation in the liver of rats","volume":"78","author":"Ozaki","year":"2014","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yamada, R., Odamaki, S., Araki, M., Watanabe, T., Matsuo, K., Uchida, K., Kato, T., Ozaki-Masuzawa, Y., and Takenaka, A. (2019). Dietary protein restriction increases hepatic leptin receptor mRNA and plasma soluble leptin receptor in male rodents. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0219603"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainres.2009.04.030","article-title":"A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins","volume":"1276","author":"Sakai","year":"2009","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0014-5793(99)00494-9","article-title":"The role of O-linked sugars in determining the very low density lipoprotein receptor stability or release from the cell","volume":"451","author":"Reina","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_26","first-page":"E107","article-title":"Females secrete growth hormone with more process irregularity than males in both humans and rats","volume":"270","author":"Pincus","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1126\/science.abn9886","article-title":"An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice","volume":"378","author":"Nikkanen","year":"2022","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1128\/MCB.06312-11","article-title":"Dynamic, sex-differential STAT5 and BCL6 binding to sex-biased, growth hormone-regulated genes in adult mouse liver","volume":"32","author":"Zhang","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1194\/jlr.M041988","article-title":"Upregulation of hepatic VLDLR via PPAR\u03b1 is required for the triglyceride-lowering effect of fenofibrate","volume":"55","author":"Gao","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1093\/ajcn\/22.5.568","article-title":"Relation of serum lipids and lipoproteins to fatty liver in kwashiorkor","volume":"22","author":"Truswell","year":"1969","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1079\/BJN19700103","article-title":"Lipid transport in kwashiorkor","volume":"24","author":"Flores","year":"1970","journal-title":"Br. J. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.nutres.2013.04.010","article-title":"A low-protein, high-carbohydrate diet increases de novo fatty acid synthesis from glycerol and glycerokinase content in the liver of growing rats","volume":"33","author":"Menezes","year":"2013","journal-title":"Nutr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5461","DOI":"10.1038\/s41598-018-23640-8","article-title":"Importance of serum amino acid profile for induction of hepatic steatosis under protein malnutrition","volume":"8","author":"Nishi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e155848","DOI":"10.1172\/jci.insight.155848","article-title":"FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk","volume":"7","author":"Chaffin","year":"2022","journal-title":"JCI Insight"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42358","DOI":"10.1074\/jbc.M204542200","article-title":"An unexpected requirement for phosphatidylethanolamine N-methyltransferase in the secretion of very low density lipoproteins","volume":"277","author":"Noga","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21851","DOI":"10.1074\/jbc.M301982200","article-title":"A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice","volume":"278","author":"Noga","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1194\/jlr.M300226-JLR200","article-title":"Insights into the requirement of phosphatidylcholine synthesis for liver function in mice","volume":"44","author":"Noga","year":"2003","journal-title":"J. Lipid Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:22:20Z","timestamp":1790655740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":37,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["nu18193153"],"URL":"https:\/\/doi.org\/10.3390\/nu18193153","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}