ρ-Coumaric acid prevents high fat and high sucrose-mediated hepatic inflammation and fibrosis.

Abstract

Chronic intake of high fat and high sucrose (HFHS) cause hepatic inflammation and fibrosis. Activation of hepatic stellate cells (HSC), which is the dominant effector during liver fibrosis, is trigged by NLR family pyrin domain containing 3 (NLRP3) inflammasome. p-coumaric acid (4-hydroxycinnamic, PCA) found in edible plants and fruits has been known as a natural bioactive component to have powerful anti-oxidant and anti-inflammatory properties. However, it is not well understood. The impact of PCA on the induced hepatic fibrosis and it’s underlying mechanism. To test this hypothesis, C57BL/6 male mice were randomized into three groups, low fat (LF) diets (11% calories from fat), high-fat diets (60% calories from fat) with high sucrose (20% sucrose, HFHS) drink, or HFHS plus PCA treatment (HFHS+PCA, 50 mg/kg b.w) by intraperitoneal injections. After feeding for 13 weeks, HFHS-fed mice increased body weight and lipid profiles with abnormal glucose metabolism compared to that of the LF diet group. Although HFHS+PCA did not make significant changes in most obesogenic parameters compared to the HFHS group, hypercholesterolemia and insulin resistance marker HOMA-IR were improved by PCA treatment. Interestingly, HFHS-induced hepatotoxicity and hepatic fibrosis which evidenced by endoplasmic reticulum (ER) stress, inflammation gene expression and collagen accumulation were significantly attenuated by PCA. We confirmed the anti-fibrogenic properties of PCA by using LX-2 hepatic stellate cells. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, which are main contributor of HSC activation, was significantly reduced by PCA in bone-marrow derived macrophages. These findings support the fact that PCA could reduce the HFHS diet-mediated hepatic fibrosis, and it is partly associated with inhibition of inflammasome.