Mechanism of Action of Saroglitazar
Saroglitazar acts as a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist with predominant PPARα activity, regulating both lipid and glucose metabolism through multiple molecular pathways.
Primary Mechanisms
PPAR Activation Profile
- Saroglitazar has significantly higher affinity for PPARα (EC50: 0.65 pmol/L) compared to PPARγ (EC50: 3 nmol/L), making it predominantly a PPARα agonist with moderate PPARγ activity 1
- This dual agonism allows it to address both lipid abnormalities (via PPARα) and insulin resistance (via PPARγ) simultaneously 2
Lipid Metabolism Effects (PPARα-mediated)
- Increases fatty acid β-oxidation in mitochondria and peroxisomes in the liver 2
- Transcriptionally activates lipid metabolizing genes in hepatocytes 2
- Reduces triglyceride synthesis and very low-density lipoprotein (VLDL) secretion 1
- Inhibits sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP) activation, preventing hepatic lipogenesis 2
Glucose Metabolism Effects (PPARγ-mediated)
- Enhances insulin sensitivity in peripheral tissues, particularly adipose tissue 2
- Regulates adiponectin and leptin levels in adipose tissue 2
- Reduces insulin resistance, leading to improved glycemic control 3
- Decreases serum insulin levels while improving glucose utilization 1
Secondary Mechanisms and Tissue-Specific Effects
Anti-inflammatory Actions
- Provides PPAR-α/γ-mediated anti-inflammatory effects by preventing phosphorylation of mitogen-activated protein kinases (JNK and ERK) 2
- Inhibits nuclear factor kappa B (NF-κB) activation in hepatocytes 2
- Modulates adhesion molecule expression and cytokine production 4
- Interferes with the transactivation capacity of signal transducers and activators of transcription (STATs) 4
Antioxidant Effects
- Activates nuclear factor erythroid 2-related factor 2 (Nrf2) 2
- Induces transcriptional expression of antioxidants from the antioxidant response element in the nucleus 2
- Reduces oxidative damage through PPARγ-mediated mechanisms 4
Anti-fibrotic Actions
- Interferes with transforming growth factor-β (TGF-β)/Smad downstream signaling 2
- Reduces collagen deposition and fibrosis progression in liver and kidney tissues 5
- Decreases TGF-β1 expression in tissues 5
Clinical Implications
Metabolic Effects
- Significantly reduces serum triglycerides (45-62%), total cholesterol (17-26%), and LDL cholesterol (11-27%) 3
- Increases HDL cholesterol levels (up to 9%) 3
- Improves glycemic parameters with HbA1c reductions of 0.7-1.6% 3
- Reduces free fatty acid levels in circulation 1
Hepatic Effects
- Decreases liver enzymes (ALT and AST) in patients with NAFLD 6
- Improves liver stiffness measurement and controlled attenuation parameter on FibroScan 6
- Reduces hepatic fat accumulation and prevents progression of NAFLD 2
Safety Profile
- Unlike some other PPAR agonists, Saroglitazar has shown minimal weight gain effects 3
- Does not appear to have significant cardiac adverse effects as seen with some other dual PPAR agonists 1
- Generally well-tolerated in clinical studies with no significant adverse events reported 3
Unique Features
- The dual PPAR-α/γ agonism provides complementary effects on both lipid and glucose metabolism, making it particularly useful for diabetic dyslipidemia 3
- The predominant PPARα activity may reduce the risk of weight gain and fluid retention typically associated with pure PPARγ agonists 1
- The combined anti-inflammatory, antioxidant, and anti-fibrotic effects make it potentially beneficial for NAFLD/NASH beyond just metabolic improvements 2