Acetaminophen‐induced liver injury is mediated by the ion channel TRPV4

Abstract

Overdosing of the analgesic acetaminophen (APAP) is one of the most common causes for acute liver failure in modern countries. Although the exact molecular mechanisms mediating hepatocellular necrosis are still elusive, it is preceded by oxidative stress triggered by excessive levels of the metabolite N‐acetyl‐para‐benzoquinone imine (NAPQI). Here, we describe the role of the redox‐sensitive transient receptor potential (TRP) ion channel TRP vanilloid 4 (TRPV4) for APAP‐induced hepatoxicity. Both pharmacological inhibition and genetic deletion of TRPV4 ameliorate APAP‐induced necrosis in mouse and human hepatocytes in vitro. Liver injury caused by a systemic overdose of APAP is reduced in TRPV4‐deficient mice and in wild‐type mice treated with a TRPV4 inhibitor. The reduction of hepatotoxicity accomplished by systemic TRPV4 inhibition is comparable to the protective effects of the antioxidant N‐acetyl‐cysteine. Although TRPV4 does not modulate intrahepatic levels of glutathione, both its inhibition and genetic deletion attenuate APAP‐induced oxidative and nitrosative stress as well as mitochondrial membrane depolarization. NAPQI evokes a calcium influx by activating heterologously expressed TRPV4 channels and endogenous TRPV4 channels in hepatoma cells but not in primary mouse hepatocytes. Taken together, our data suggest that TRPV4 mediates APAP‐induced hepatotoxicity and thus may be a suitable target for treatment of this critical side effect.—Echtermeyer, F., Eberhardt, M., Risser, L., Herzog, C., Gueler, F., Khalil, M., Engel, M., Vondran, F., Leffler, A. Acetaminophen‐induced liver injury is mediated by the ion channel TRPV4. FASEB J. 33, 10257–10268 (2019). http://www.fasebj.org

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“…Despite its clear promise, some potential restrictions and caveats should not go unmentioned. First, systemic inhibition of TRPV4 could prove problematic because of potential effects on hepatic function, a concern that is particularly relevant in the critically ill (38), yet a hepatoprotective role of TRPV4 inhibition has also been postulated in acetaminophen toxicity (12). Notably, phase I clinical trials using a selective TRPV4 inhibitor did not detect increased liver enzymes in healthy volunteers or patients with congestive heart failure (17).…”

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

“…Another study by Echtermeyer and colleagues suggests that TRPV4 may also contribute to acetaminophen-initiated hepatocyte toxicity [ 69 ]. Liver damage, assessed by measurement of blood liver marker enzymes and liver histology, was substantially reduced in TRPV4 knockout mice compared to that in wild-type mice, and in wild-type mice treated with the TRPV4 inhibitor HCO67047.…”

“…Patch clamp recording with HEK293T cells heterologously expressing TRPV4 showed that NAPQI activates a current with the characteristics of TRPV4. However, such a NAPQI-activated current was not observed in isolated mouse and human hepatocytes [ 69 ]. Further experiments are required to confirm that TRPV4 proteins are present in the hepatocyte plasma membrane and do, indeed, form functional TRPV4 channels in freshly isolated hepatocytes.…”

“…Moreover, the depletion of glutathione impairs the capacity of hepatocytes to remove ROS, generated as a result of liver injury induced by NAPQI [64,68]. This combination of events leads to mitochondrial dysfunction, decreased ATP production, and increases in ROS and in [Ca 2+ ] cyt , culminating in necrotic cell death [15,26,29,30,61,64,68,69]. Acetaminophen is initially metabolised by UDP-glucuronosyl transferase, sulfotransferase, and cytochrome P450 2E1 (green arrows).…”

TRPV4 integrates matrix mechanosensing with Ca2+ signaling to regulate extracellular matrix remodeling

“…While no studies have directly evaluated liver fibrosis in TRPV4 KO mice, some data suggest that the absence of TRPV4 may be protective. TRPV4 KO mice exhibited reduced hepatotoxicity caused by high levels of acetaminophen, which can progress to liver fibrosis if lethality from acute liver failure does not occur first [140,141]. TRPV4 inhibition also reduced the activation of hepatic stellate cells, the matrix remodeling cells of the liver [142].…”