Introduction and Objective: PAQR4, an orphan receptor within the progestin and adipoQ receptor family (PAQR1-11), is implicated in multiple cancers, including hepatocellular carcinoma (HCC). However, its metabolic function in hepatocytes remains unclear. Our recent findings identify PAQR4 as a key regulator of ceramide metabolism. In adipocytes, PAQR4 overactivation leads to ceramide accumulation, disrupting adipose tissue function and systemic metabolic health, whereas its deletion mitigates obesity-induced metabolic dysfunction.Methods: To investigate its liver function, we developed doxycycline (dox)-inducible hepatocyte-specific transgenic (Paqr4-Tg) and knockout (Paqr4-LKO) mouse models.Results: Induction of Paqr4 in hepatocytes caused transient weight loss due to reduced food intake, accompanied by hypoglycemia, decreased hepatic glycogen, and suppression of gluconeogenic genes, indicating impaired hepatic glucose production. Metabolic cage analysis revealed a shift toward fat oxidation, as reflected by a lower respiratory exchange ratio. In addition, Paqr4-Tg mice exhibited elevated circulating NEFA levels and enhanced adipose lipolysis. Similar weight reduction and hypoglycemia was observed under obese conditions. In contrast, Paqr4-LKO mice exhibited relatively modest systemic metabolic changes in obesity despite alterations in hepatic carbohydrate and lipid metabolism, as suggested by gene ontology analysis. Consistent with its effects in adipocytes, PAQR4 promoted hepatic ceramide accumulation. Furthermore, PAQR4 increased the secretion of hepatokine FGF21 and circulating bile acid levels, potentially promoting the liver-adipose tissue communication and the lipolytic pathway in adipose tissues.Conclusion: These findings position PAQR4 as a critical regulator of hepatic metabolism, modulating ceramide homeostasis and hepatokine signaling. Further investigation is needed to elucidate its role in metabolic-associated steatohepatitis (MASH) and HCC progression.
Q. Zhu: None. P.E. Scherer: None.
American Heart Association (AHA855170); National Institutes of Health
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