| First Author | Gross B | Year | 2011 |
| Journal | Br J Pharmacol | Volume | 164 |
| Issue | 1 | Pages | 192-208 |
| PubMed ID | 21426320 | Mgi Jnum | J:211453 |
| Mgi Id | MGI:5575465 | Doi | 10.1111/j.1476-5381.2011.01359.x |
| Citation | Gross B, et al. (2011) Generation and characterization of a humanized PPARdelta mouse model. Br J Pharmacol 164(1):192-208 |
| abstractText | BACKGROUND AND PURPOSE: Humanized mice for the nuclear receptor peroxisome proliferator-activated receptor delta (PPARdelta), termed PPARdelta knock-in (PPARdelta KI) mice, were generated for the investigation of functional differences between mouse and human PPARdelta and as tools for early drug efficacy assessment. EXPERIMENTAL APPROACH: Human PPARdelta function in lipid metabolism was assessed at baseline, after fasting or when challenged with the GW0742 compound in mice fed a chow diet or high-fat diet (HFD). KEY RESULTS: Analysis of PPARdelta mRNA levels revealed a hypomorph expression of human PPARdelta in liver, macrophages, small intestine and heart, but not in soleus and quadriceps muscles, white adipose tissue and skin. PPARdelta KI mice displayed a small decrease of high-density lipoprotein-cholesterol whereas other lipid parameters were unaltered. Plasma metabolic parameters were similar in wild-type and PPARdelta KI mice when fed chow or HFD, and following physiological (fasting) and pharmacological (GW0742 compound) activation of PPARdelta. Gene expression profiling in liver, soleus muscle and macrophages showed similar gene patterns regulated by mouse and human PPARdelta. The anti-inflammatory potential of human PPARdelta was also similar to mouse PPARdelta in liver and isolated macrophages. CONCLUSIONS AND IMPLICATIONS: These data indicate that human PPARdelta can compensate for mouse PPARdelta in the regulation of lipid metabolism and inflammation. Overall, this novel PPARdelta KI mouse model shows full responsiveness to pharmacological challenge and represents a useful tool for the preclinical assessment of PPARdelta activators with species-specific activity. |
