Sex Differences in Hepatic VLDLR Response to Protein Restriction and Its Relationship with Hepatic Lipid Accumulation

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.