TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity

Abstract

NAFLD is a clinically progressive disease with steatosis, inflammation, endothelial dysfunction and fibrosis being the stages where clinical intervention becomes necessary. Lack of early biomarkers and absence of a FDA approved drug obstructs efforts for effective treatment. NAFLD progression is strongly linked to a balance between liver injury, tissue regeneration and the functioning of endogenous defense mechanisms. The failure of the defense pathways to resist the tissue damage arising from redox stress, one of the “multiple hits” in disease progression, give rise to heightened inflammation and occasional fibrosis. We introduce an endogenous defense mechanism in the liver that is mediated by TRPV4, a transient receptor potential calcium-permeable ion channel that responds to the cytotoxic liver environment and negatively regulates CYP2E1, a cytochrome p450 enzyme. Using Trpv4−/− mice and cultured primary cells, we show that TRPV4 is activated both by damage associated molecular pattern HMGB1 and collagen in diseased Kupffer cells that in turn activate the endothelial NOS (NOS3) to release nitric oxide (NO). The diffusible NO acts in a paracrine fashion in neighboring hepatocytes to deactivate the redox toxicity induced by CYP2E1. We also find that CYP2E1-mediated TRPV4 repression in late stages causes an unrestricted progression of disease. Thus, TRPV4 functions as a sensor of cell stress in the diseased fatty liver and constitutes an endogenous defense molecule, a novel concept with potential for therapeutic approaches against NAFLD, perhaps also against hepatic drug toxicity in general.

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

“…Previous reports suggested that TRPV4 is expressed in both hepatoma cell lines and primary hepatocytes (16)(17)(18)(19). Indeed, by performing RT-PCR on Huh7, HepG2, and PHH cells as well as PMHs, we could confirm an expression of TRPV4 in these cells (Supplemental Fig.…”

“…The ion channel TRP vanilloid 4 (TRPV4) is expressed in several tissues and is involved in diverse physiologic functions by sensing osmolarity, pressure, and heat but also reactive oxygen species (ROS) (14,15). Other than that TRPV4 was shown to be expressed in both hepatoma cell lines and native hepatocytes, little is known about the role of TRPV4 in the liver (16)(17)(18)(19). However, TRPV4 mediates ROS-induced cell damage associated with ischemia and reperfusion in both cardiomyocytes and in the CNS (20)(21)(22)(23).…”

Pharmacological Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Alleviates Carbon Tetrachloride-Induced Liver Fibrosis in Mice

“…2). maintenance of vascular function 10,13 . Abnormal expres-sion of TRPV and alteration of its channel activity are associated with many diseases 6 .…”

Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach

“…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).…”