Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 21:2022:3100943.
doi: 10.1155/2022/3100943. eCollection 2022.

Transient Receptor Potential Vanilloid-1 (TRPV1) Alleviates Hepatic Fibrosis via TGF- β Signaling

Ke Qian  1 , Xiaohua Lei  1   2 , Guoxing Liu  1 , Yu Fang  1 , Chengzhi Xie  1 , Xiaolong Wu  1 , Qiang Liu  1 , Gao Liu  1 , Zhenyu Cao  1 , Ju Zhang  1 , Tao Kuang  1 , Likun Yan  1 , Jie Fu  1 , Huihui Du  1 , Zhiqiang Liu  1 , Yuan Chu  1 , Ge Xu  1 , Hirofumi Yamamoto  3 , Masaki Mori  4 , Xin M Liang  5 , Xundi Xu  1   6
Affiliations

Transient Receptor Potential Vanilloid-1 (TRPV1) Alleviates Hepatic Fibrosis via TGF- β Signaling

Ke Qian et al. Dis Markers. .

Abstract

Hepatic fibrosis is a major global health problem and considered a leading cause of liver-related morbidity and mortality worldwide. Although previous studies have suggested that transient receptor potential vanilloid-1 (TRPV1) is protective against cardiac and renal fibrosis, its functional role in hepatic fibrosis has remained elusive. Herein, we characterize the effects of TRPV1 on carbon tetrachloride- (CCl4-) induced mice, in vitro transforming growth factor-β- (TGF-β-) treated hepatic stellate cells (HSCs), and human fibrosis specimens. Finally, our results demonstrated the significant TRPV1 downregulation in human liver fibrosis tissues. Knocking out TRPV1 significantly increased the expression of various hepatic fibrosis markers, while the expression of these biomarkers declined markedly in capsaicin-activated mice. Moreover, our study revealed that knocking down TRPV1 would enhance the promotive effect of TGF-β on HSC proliferation, cell cycle, cell apoptosis, and ECM expression. Also, such promotive effect can be partially reversible by capsaicin, an exogenous activator of TRPV1. Collectively, the obtained data suggest that TRPV1 may alleviate CCl4-induced hepatic fibrosis and attenuate the effect of TGF-β on HSC activation, proliferation, and apoptosis, which overall implies that targeting TRPV1 channel activity may be an effective therapeutic strategy for treating hepatic fibrosis.

PubMed Disclaimer

Conflict of interest statement

The authors declared no conflict of interest.

Figures

Figure 1
Figure 1
TRPV1 modulates CCl4-induced hepatic fibrosis in mice, and its expression is downregulated in human liver fibrosis. (a) TRPV1 protein expression in TRPV1−/− mice was measured through Western blot analysis. (b) Morphology of whole livers and H&E-stained liver sections (400x magnification) from the four CCl4-induced hepatic fibrosis models (WT with capsaicin intraperitoneal injection, WT with DMSO intraperitoneal injection, WT, TRPV1−/−, all under CCl4 treatment). (c) Pathological morphology of the four animal models was shown by picro-sirius red staining. (d) Quantitative analysis of the fibrosis area. Data are presented as mean ± SD (n = 5 mice). ∗∗∗p < 0.001. (e) Representative immunohistochemistry images of TRPV1 expression in normal control liver and liver fibrosis. (f) The semiquantitative levels of TRPV1 expression by immunohistochemistry in liver paraffin sections from 10 normal control and 40 liver fibrosis patients. ∗∗p < 0.001. Data are presented as mean ± SD.
Figure 2
Figure 2
Protective effect of TRPV1 on the CCl4-induced mouse model. (a–d) The serum concentration levels of hyaluronic acid, collagen type IV, laminin, and precollagen type III in the indicated four groups were determined using radioimmunoassay kits. (e, f) ALT and AST in serums derived from mice from four different groups were determined by standard enzymatic assay kits. Data are presented as mean ± SD of three independent experiments. (g–i) The protein levels of α-SMA and COL1A1 in liver tissues from the four groups were determined using Western blot analyses. (j–n) The activity of SOD, CuZnSOD, T-AOC, GSHPX, and MDA was determined in the liver tissues of the four groups of mice. Data are presented as mean ± SD (n = 5 mice). ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001.
Figure 3
Figure 3
The expression of TRPV1 in TGF-β-treated HSCs and TRPV1 knockdown enhances TGF-β-induced ECM protein expression. (a, b) HSCs were exposed to 5 ng/ml TGF-β stimulation or (and) transfected with si-TRPV1; TRPV1 protein expression in HSCs was determined through Western blot analysis. Data are presented as mean ± SD (n = 5, ∗p < 0.05, ∗∗∗p < 0.001). (c) The proliferation of si-TRPV1-transfected HSC in the presence or absence of TGF-β stimulation was determined using MTT assay. The obtained results are presented as mean ± SD (n = 5, ∗∗∗p < 0.001). (d) The proliferation of HSC was determined using BrdU assay. The obtained results are presented as mean ± SD (n = 5, ∗p < 0.05, ∗∗∗p < 0.001, compared with the si-NC (negative control) group; #p < 0.05, compared with the si-NC+TGF-β group). (e, f) The protein levels of α-SMA and COL1A1 in si-TRPV1-transfected HSC in the presence or absence of TGF-β1 stimulation were determined using Western blots. Data are presented as mean ± SD (n = 5, ∗∗p < 0.01, ∗∗∗p < 0.001 compared with the si-NC group; ###p < 0.001, compared with the si-NC+TGF-β group).
Figure 4
Figure 4
Capsaicin can partially reverse the effect of TGF-β on HSCs. (a, b) HSCs were cotreated with 5 ng/ml TGF-β and a series of doses of capsaicin (0, 50, and 100 μM); HSC proliferation was determined using MTT and BrdU assays. (c, d) HSCs were treated with 100 μM capsaicin or 5 ng/ml TGF-β or cotreated by both; the cell cycle of HSCs was determined using flow cytometry. (e, f) The cell apoptosis rate was determined using flow cytometry. (g) α-SMA and COL1A1 contents were shown using IF assays. (h, i) Western blot analysis on protein levels of α-SMA and COL1A1 was conducted. Data are presented as mean ± SD of five independently repeated experiments. ∗p < 0.1, ∗∗∗p < 0.001, compared with the control group; #p < 0.1, ###p < 0.001, compared with the 0 μM capsaicin+TGF-β group or TGF-β only group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Asrani S. K., Devarbhavi H., Eaton J., Kamath P. S. Burden of liver diseases in the world. Journal of Hepatology . 2019;70(1):151–171. doi: 10.1016/j.jhep.2018.09.014. - DOI - PubMed
    1. She S., Wu X., Zheng D., et al. PSMP/MSMP promotes hepatic fibrosis through CCR2 and represents a novel therapeutic target. Journal of Hepatology . 2020;72(3):506–518. doi: 10.1016/j.jhep.2019.09.033. - DOI - PubMed
    1. Friedman S. L., Pinzani M. Hepatic fibrosis 2022: unmet needs and a blueprint for the future. Hepatology . 2022;75(2):473–488. doi: 10.1002/hep.32285. - DOI - PubMed
    1. Gines P., Castera L., Lammert F., et al. Population screening for liver fibrosis: toward early diagnosis and intervention for chronic liver diseases. Hepatology . 2022;75(1):219–228. doi: 10.1002/hep.32163. - DOI - PubMed
    1. Bataller R., Brenner D. A. Liver fibrosis. The Journal of Clinical Investigation . 2005;115(2):209–218. doi: 10.1172/JCI24282. - DOI - PMC - PubMed

MeSH terms