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Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ
Huijun He1,2,3, Yu Zhong2, Honglian Wang2
1Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Abstract:
Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.
Insights
Targeting Smad3 signaling protects against type 2 diabetes complications. Inhibiting Smad3 in mice improved blood glucose, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD).
Area of Science:
- Metabolic diseases
- Molecular biology
- Genetics
Background:
- Transforming growth factor-β (TGF-β)/Smad3 signaling is implicated in fibrotic and inflammatory diseases.
- The specific role of Smad3 in type 2 diabetes-associated dyslipidemia and non-alcoholic fatty liver disease (NAFLD) is not well understood.
- Therapeutic potential of targeting Smad3 for these metabolic abnormalities remains unexplored.
Purpose of the Study:
- To investigate the role of Smad3 in dyslipidemia and NAFLD in type 2 diabetes.
- To explore the therapeutic effects of Smad3 inhibition on these metabolic conditions.
Main Methods:
- Utilized Smad3 knockout (KO) db/db mice and Smad3 wild-type (WT) db/db mice.
- Administered a Smad3-specific inhibitor (SIS3) to db/db mice.
- Employed RNA-sequencing to identify Smad3-target genes involved in lipid metabolism.
Main Results:
- Smad3 KO db/db mice exhibited protection against dyslipidemia and NAFLD compared to WT db/db mice.
- SIS3 treatment improved blood glucose levels, diabetic dyslipidemia, and NAFLD in db/db mice.
- Smad3 was found to target peroxisome proliferator-activated receptor delta (PPARδ), contributing to dyslipidemia and NAFLD.
Conclusions:
- Smad3 plays a critical role in the development of dyslipidemia and NAFLD in the context of type 2 diabetes.
- Genetic deletion or pharmacological inhibition of Smad3 offers a potential therapeutic strategy for managing metabolic abnormalities in type 2 diabetes.
- Targeting the Smad3-PPARδ axis presents a novel therapeutic avenue for treating diabetic metabolic disorders.
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