Effect of celastrol on toll‑like receptor 4‑mediated inflammatory response in free fatty acid‑induced HepG2 cells

Abstract

Toll-like receptor 4 (TLR4)-mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phospho-NF-κBp65, as well as of the downstream inflammatory cytokines interleukin-1β and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFA-induced inflammatory response. In addition, co-treatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4-mediated immune and inflammatory response in steatotic HepG2 cells.

Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B

“…Moreover, Song et al (2018) revealed that arachidonic acid (AA), a kind of PUFA, inhibited HBV infection. It might be because FFAs were potential ligands for toll-like receptor 4 (TLR4) and could activate the innate immune response ( Mamedova et al, 2013 ; Han et al, 2018 ).…”

Antitumor activity of celastrol by inhibition of proliferation, invasion, and migration in cholangiocarcinoma via PTEN/PI3K/Akt pathway

“…An SY demonstrated that celastrol can significantly suppress microbial processes . According to the recent discovery, celastrol exhibits an antitumor effect on several cancer cells through inhibiting cell survival, invasion/migration, and angiogenesis or promoting cell apoptosis in a wide variety of tumor models, including osteosarcoma, colorectal cancer, liver cancer, lung cancer, and breast cancer . Mechanically, celastrol meditates tumor‐related proinflammatory cytokines, adhesion molecules, TGF‐activated kinase 1 (TAK1), NF‐kB, CXCR4, VEGF receptor (VEGFR), proteasome, and STAT3 .…”

Regulatory mechanisms of energy metabolism and inflammation in oleic acid‐treated HepG2 cells from Lactobacillus acidophilus NX2‐6 extract

“…of lipid metabolism (Park et al, 2013), mitochondrial dysfunction (Rafiei et al, 2019), oxidative stress (Yan et al, 2016), endoplasmic reticulum (ER) stress (Wang et al, 2018), and metabolic inflammation (Han et al, 2018) in the hepatic cells. Although some former researches have unraveled pathogenic mechanisms of NAFLD, effective therapies for alleviating NAFLD remain to be determined (Wang et al, 2018).…”