ATP-citrate lyase inhibitor improves ectopic lipid accumulation in the kidney in a db/db mouse model

by Selleckchem | Sep 05 2023

Aim: We evaluated a novel treatment for obesity-related renal, an ATP-citrate lyase (ACL) inhibitor, to attenuate ectopic lipid accumulation (ELA) in the kidney and the ensuing inflammation.

Materials and methods: An ACL inhibitor was administered intragastrically to 12-week-old db/db mice for 30 days. The appearance of ELA was observed by staining kidney sections with Oil Red O, and the differences in tissue lipid metabolites were assessed by mass spectrometry. The anti-obesity and renoprotection effects of ACL inhibitors were observed by histological examination and multiple biochemical assays.

Results: Using the AutoDock Vina application, we determined that among the four known ACL inhibitors (SB-204990, ETC-1002, NDI-091143, and BMS-303141), BMS-303141 had the highest affinity for ACL and reduced ACL expression in the kidneys of db/db mice. We reported that BMS-303141 administration could decrease the levels of serum lipid and renal lipogenic enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), HMG-CoA reductase (HMGCR), and diminish renal ELA in db/db mice. In addition, we found that reducing ELA improved renal injuries, inflammation, and tubulointerstitial fibrosis.

Conclusion: ACL inhibitor BMS-303141 protects against obesity-related renal injuries.

Comments:

This study aimed to evaluate the effectiveness of a novel treatment for obesity-related renal issues using an ATP-citrate lyase (ACL) inhibitor. The researchers administered the ACL inhibitor intragastrically to db/db mice, which are commonly used as a model for obesity-related conditions, for a period of 30 days. They observed the presence of ectopic lipid accumulation (ELA) in the kidney by staining kidney sections with Oil Red O and analyzed the differences in tissue lipid metabolites using mass spectrometry. They also examined the anti-obesity and renoprotective effects of the ACL inhibitor through histological examination and multiple biochemical assays.

The researchers used the AutoDock Vina application to determine the ACL inhibitor with the highest affinity for ACL among four known inhibitors (SB-204990, ETC-1002, NDI-091143, and BMS-303141). They found that BMS-303141 exhibited the highest affinity for ACL and reduced ACL expression in the kidneys of db/db mice. Furthermore, the administration of BMS-303141 resulted in decreased levels of serum lipids and renal lipogenic enzymes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and HMG-CoA reductase (HMGCR). It also reduced renal ELA in the db/db mice. Importantly, reducing ELA led to improvements in renal injuries, inflammation, and tubulointerstitial fibrosis.

In conclusion, the ACL inhibitor BMS-303141 demonstrated protective effects against obesity-related renal injuries in this study. The administration of the inhibitor resulted in reduced serum lipid levels, decreased expression of renal lipogenic enzymes, and attenuation of ELA in the kidney. These findings suggest that ACL inhibition could be a potential therapeutic strategy for treating renal complications associated with obesity.