Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ

• Published in: International journal of molecular sciences Vol. 24; no. 14; p. 11396
• Main Authors: He, Huijun, Zhong, Yu, Wang, Honglian, Tang, Patrick Ming-Kuen, Xue, Vivian Weiwen, Chen, Xiaocui, Chen, Jiaoyi, Huang, Xiaoru, Wang, Cheng, Lan, Huiyao
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2023; MDPI
• Subjects: Blood sugar; Cholesterol; Diabetes; Diabetic nephropathy; Diagnostic reagents industry; Disease; dyslipidemia; Fatty acids; Fatty liver; Health aspects; High density lipoprotein; Hyperglycemia; Insulin resistance; Lipids; Liver; Metabolic disorders; Physiological aspects; Scientific equipment and supplies industry; Smad3; Smad3 inhibitor; Transforming growth factors; treatment; Type 2 diabetes; United States; China; Smad3 inhibitor; treatment; Smad3; fatty liver; dyslipidemia; diabetes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241411396

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)- mice and by treating mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)- mice, Smad3 KO- mice were protected against dyslipidemia and NAFLD. Similarly, treatment of 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 mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3.