Hepatic Scavenger Receptor Class B Type 1 Knockdown Reduces Atherosclerosis and Enhances the Antiatherosclerotic Effect of Brown Fat Activation in APOE*3-Leiden.CETP Mice.

Enchen Zhou,Patrick C N Rensen,Cong Liu,Amanda C Foks,Yanan Wang,Hiroyuki Nakashima,Zhuang Li,Jimmy F P Berbée,Ko Willems Van Dijk,Zhixiong Ying

doi:10.1161/atvbaha.121.315882

Abstract

[Figure: see text].

Highlights

To investigate the role of hepatic SRB1 in the beneficial effects of brown fat activation on cholesterol metabolism and atherosclerosis development, E3L.CETP mice were injected with short hairpin RNA (shRNA)-loaded adenoassociated virus serotype 8 (AAV8) to downregulate liver-specific expression of SRB1.15 Hepatic SRB1 was downregulated by ≈40% to 55% at both mRNA and protein level as compared with control mice, as assessed after 11 weeks of injection upon termination (Table; Figure IA and IB in the Data Supplement). shSRB1-AAV8 did not reduce SRB1 protein levels in both adrenal glands and gonadal white adipose tissues (Figure IE and IF in the Data Supplement), while it increased SRB1 protein levels in descending thoracic aortas (+48%, Figure IG in the Data Supplement)
Two weeks after shSRB1-AAV8 injection, both control and SRB1 knockdown mice were treated with vehicle or the β3-AR agonist CL316 243 to activate brown fat. β3AR agonism prevented body weight gain and decreased gonadal white adipose tissue and intrascapular brown adipose tissue) mass in control mice, which is in line with our previous observations,[7] confirming the beneficial effects of β3-AR agonism on adiposity, and which was observed in hepatic SRB1 knockdown mice (Figure IIA through IIC in the Data Supplement)
We explored the effects of hepatic SRB1 knockdown on the plasma lipid-modulating effects of brown fat activation

Summary

Methods

The authors declare that all supporting data are available within the article and its Data Supplement. Additional detailed materials and methods are included in the Data Supplement. Hemizygous APOE*3-Leiden (E3L) mice were crossbred with homozygous human CETP (cholesteryl ester transfer protein) transgenic mice to generate heterozygous E3L.CETP mice.[16] Please see the Major Resources Table in the Data Supplement. Mice were housed in standard conditions at room temperature (22 °C) with 40±5% relative humidity and a 12-h light/dark (7 am lights on; 7 pm lights off) cycle. Water and standard laboratory diet (801203, Special Diets Services, United Kingdom) were available ad libitum, unless indicated

Results

Discussion

Conclusion