Purpose of the Study: Dyslipidemia is one of the diabetic complications which is relevant to the disorder of interaction between glucose and lipid metabolism. In our preliminary studies, we found that Smad3 is the key pathogenic mediator in db/db mice. Metabolic symptoms in diabetes are improved in Smad3KO-db/db mice. Thus, we hypothesized that Smad3 is a therapeutic target for treatment of dyslipidemia in type 2 diabetes.

Methods: db/db mice were treated with Smad3 inhibitor SIS3 at the age of 4 weeks at the dose of 2.5mg/kg bw/day by intra peritoneal injection for 8 weeks. Control group db/db mice were treated with SIS3 solvent only. Molecules and cytokines involved in lipid metabolism were examined by Realtime-PCR, Western blotting, immunohistochemistry, ELISA for in vivo and in vitro experiments. The mechanism of Smad3 signaling interfering lipid metabolism was studied by Chip-sequencing and RNA sequencing.

Summary of the results: Blood high density lipoprotein (HDL) level was up regulated while low density lipoprotein (LDL) level and triglycerides were down regulated in Smad3 KO mice, which showed Smad3 is one of the main regulators in lipid metabolism. SIS3 treated mice showed significantly improved glycemia, lipidemia. Insulin sensitivity was ameliorated in SIS3 treatment group compared with control group. SIS3 treated Hepg2 cells and AML12 cells showed lower lipid absorbance than control group. RNA sequencing revealed that differentially expressed genes (DEGs) in concentrations of apolipoproteins A1 (ApoA1) was notable enriched in liver of Smad3KO mice, which also showed APOA1 has direct binding site with Smad3. We subsequently found that APOA1 was negatively regulated by Smad3 signaling therefore influence the lipid metabolism in type 2 diabetes.

Conclusion: Smad3 is a pathogenic mediator of diabetic metabolism. Treatment of type 2 diabetic mice with Smad3 inhibitor SIS3 improves lipidemia by enhancing the activity of DEGs in APOA1.


H. He: None. X. Huang: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. H. Lan: None.

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