Lysophosphatidic Acid Receptor 6 Inhibits Hepatocyte Function Following Repopulation after Partial Hepatectomy

Objective: In addition to coordinated mitogenesis following partial-hepatectomy (PHx), hepatocytes must regain cell orientation-functionality. LPAR6 is the most abundant hepatic LPAR subtype, and is transiently increased following PHx and chronically elevated in human HCC. In this study we developed a LPAR6 knockout mouse (LPAR6−/−) to study LPAR6 function during hepatic regeneration Methods: A 2/3 PHx was performed on LPAR6−/− and wild-type C57BL/6 (WT) mice. Tissue and serum were collected and analyzed for markers of hepatic regeneration and liver function. Results: No phenotypic differences were observed between LPAR6−/− and WT prior to PHx. Both groups exhibited normal hepatic histology and metabolic parameters, and no compensatory change in hepatic LPAR1-5 expression was detected in LPAR6−/−. In male LPAR6−/−, PHx induced jaundice in 66% of animals within 96 hrs. In females, 32% of mice died within 72Hrs of PHx. In animals survived to 7d, no significant difference in regenerated liver weight occurred for male or female LPAR6−/− vs WT. Metabolic analysis revealed significantly elevated bilirubin, ALT/AST, GGT, alkaline phosphatase, creatinine, and cholesterol in male mice 72-96 hrs post-PHx compared to WT. No significant differences in corresponding parameters were detected between female LPAR6−/− and WT. Histology revealed slower rate of portal triad formation in LPAR6−/− mice post-PHx. Conclusion: LPAR6 deletion does not affect normal liver development-architecture, or rate of hepatocyte repopulation post-PHx. However, LPAR6−/− profoundly impacts hepatic function after PHx, suggesting LPAR6 may be involved in regulating hepatocyte orientation and/or bile production. Overall, male mice appear better adapted to overcome LPAR6 deletion following PHx than females.