Role of TRP Channels in Liver-Related Diseases

Abstract

The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver's normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases.

Keywords: TRP channels; hepatocellular carcinoma; liver diseases; liver fibrosis; liver injury.

Figure 1

TRPC1, TRPV1, TRPV4, TRPM2, and TPM7 mediate APAP-induced liver injury. The intracellular metabolite of APAP, NAPQI, directly activates TRPC1 and TRPV1 to trigger Ca²⁺ influx and induce mitochondrial oxidative stress. It eventually leads to the activation of RIP3 and translocation of Drp1 and Bax to the mitochondria, triggering mitochondrial membrane permeability transition. In addition, NAPQI protein adducts modulate respiratory chain function similarly inducing mitochondrial oxidative stress responses. TRPM2 and TRPM7 channels activated by ROS and ADPR further aggravate intracellular cation concentrations, forming a vicious cycle and ultimately causing apoptosis.

Figure 2

TRPM8 mediates the process of liver fibrosis. Activation of TRPM8 upregulates the inflammation-related factor S100A9 and downregulates the liver-specific gene expression regulator HNF4α while increasing the number of F4/80-positive cells, which in turn promotes the activation of HSCs and cholangiocytes and thereby mediates liver fibrosis.

Figure 3

TRPC6 mediates the process of liver fibrosis. TRPC6 is significantly upregulated under hypoxic conditions in a manner dependent on NICD activation. TRPC6 promotes α-SMA and collagen expression through the activation of calcineurin and SMAD2/3, leading to liver fibrosis.

Figure 4

Adriamycin enters BNL1 ME cells of the hepatoma cell line through TRPV2. CBD and 2-APB act as agonists of TRPV2 to activate and open the TRPV2 channel, promoting the entry and massive accumulation of doxorubicin in BNL1 ME cells. Meanwhile, CBD inhibits P-gp ATPase, thereby reducing doxorubicin removal from cells.

Figure 5

COX-2 and PGE2 levels were significantly decreased in venom peptide (Tv1)-treated 1MEA cells. Tv1 prevented Ca²⁺ influx after binding to TRPV6 and TRPC6, and the transcription factor NFAT could not be dephosphorylated by calcineurin, thus downregulating COX-2 expression.