Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Dec;392(12):1569-1576. doi: 10.1007/s00210-019-01703-5. Epub 2019 Jul 31.
Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6 weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.
肝纤维化是一种全球性的健康挑战，源于慢性肝损伤，目前尚无有效的治疗方法。已经表明，不同过氧化物酶体增殖物激活受体（PPAR）同工型（α、γ 和 δ）的激活剂可以影响肝纤维化的不同途径。为了评估双重 PPAR-α/γ 激动剂沙格列汀（SGZ）对硫代乙酰胺（TAA）诱导的大鼠纤维化的影响，SGZ 与 TAA 注射一起给药 6 周。SGZ 给药可改善 TAA 诱导的肝生物标志物升高。SGZ 能够抑制门脉周围和小叶内纤维结缔组织增殖，降低羟脯氨酸含量，并降低α平滑肌肌动蛋白（α-SMA）蛋白表达。为了揭示 SGZ 的抗纤维化机制，研究了几种纤维化标志物的作用。SGZ 对瘦素、转化生长因子-β1（TGF-β1）和血小板衍生生长因子-BB（PDGF-BB）的蛋白水平具有抑制作用。此外，SGZ 通过降低组织金属蛋白酶抑制剂-1（TIMP-1）来纠正基质降解。这项研究表明，SGZ 可能通过抑制瘦素发挥抗纤维化作用，瘦素可以抑制 TGF-β1 和 PDFG-BB，随后抑制 TIMP-1。
