Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway

Abstract

Background and Purpose

Cholesterol is an essential lipid and its homeostasis is a major factor for many diseases, such as hyperlipidemia, atherosclerosis, diabetes, and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Cana) is a new kind of hypoglycemic agent, which decreases urinary glucose reabsorption and reduces hyperglycemia. Cana has been shown to regulate serum lipid, decrease serum triglyceride and increase serum high-density lipoprotein-cholesterol (HDL-C), and improve cardiovascular outcomes. But evidence of how Cana impacted the cholesterol metabolism remains elusive.

Methods

We treated Cana on mice with chow diet or western diet and then detected cholesterol metabolism in the liver and intestine. To explore the mechanism, we also treated hepG2 cells and Caco2 cells with different concentrations of Cana.

Results

In this study, we showed that Cana facilitated hepatic and intestinal cholesterol efflux. Mechanically, Cana via activating adenosine monophosphate-activated protein kinase (AMPK) increased the expression of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in liver and intestine, increased biliary and fecal cholesterol excretion.

Conclusion

This research confirms that Cana regulates cholesterol efflux and improves blood and hepatic lipid; this may be a partial reason for improving cardiovascular disease.

Keywords:

• canagliflozin
• ATP-binding cassette (ABC) transporters G5/8
• cholesterol efflux
• AMPK

Acknowledgments

We thank the Laboratory of Pathology, West China Hospital, for technical assistance.

Abbreviations

Abcg5/8, ATP-binding cassette transporters 5/8; AMPK, adenosine monophosphate-activated protein kinase; Abca1, ATP-binding cassette transporters A1; Abcg1, ATP-binding cassette transporters G1; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; SGLT2, sodium glucose cotransporter 2; NPC1L1, Niemann-Pick C1-Like 1; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS, 3-hydroxy-3-methylglutaryl-CoA synthase; LXR, liver X receptor; FXR, farnesoid X receptor; ALT, serum alanine transaminase; AST, aspartate aminotransferase; CD, chow diet; WD, western diet; Cana, canagliflozin; CC, compound C.

Author Contributions

Y.Z. designed and performed experiments and wrote the manuscript. Y. L., Q. L., Q.T., J. Z., Z.Z. and C. H. contributed to the discussion and review of the manuscript. H.H., G.Z., J. Z., J.Y. and Y.X. helped with experiments. J. H. and Z.Z. obtained funding, designed experiments, and wrote the manuscript. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval for the version to be published; and agreed to be accountable for all aspects of the work.

Disclosure

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81930020, 81603035 and 81870599), China Postdoctoral Fellowship (2017M612981), Young Scientist Fellowship of Sichuan University (2017SCU11026), and Postdoctoral Fellowship of Sichuan University (2017SCU12036).