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

Zishun Zhan; Aimei Li; Wei Zhang; Xueqin Wu; Jinrong He; Zhi Li; Yanchun Li; Jian Sun; Hao Zhang

doi:10.3389/fendo.2022.914865

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

Front Endocrinol (Lausanne). 2022 Dec 8:13:914865. doi: 10.3389/fendo.2022.914865. eCollection 2022.

Authors

Zishun Zhan^{1

2}, Aimei Li^{1

2}, Wei Zhang^{1

2}, Xueqin Wu^{1

2}, Jinrong He^{1

2}, Zhi Li^{1

2}, Yanchun Li³, Jian Sun^{1

2

4}, Hao Zhang^{1

2}

Affiliations

¹ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
² The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan, China.
³ Division of Biological Sciences, Department of Medicine, University of Chicago, Chicago, Chicago, IL, United States.
⁴ Department of Rheumatology and Immunology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

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.

Keywords: ACL; ATP-citrate lyase; BMS-303141; ectopic lipid accumulation; obesity-related nephropathy; renal inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate
Animals
Enzyme Inhibitors* / pharmacology
Enzyme Inhibitors* / therapeutic use
Inflammation
Kidney*
Mice
Obesity

Substances

citrate (pro-3S)-lyase
Enzyme Inhibitors
Adenosine Triphosphate