Authors:
Lim MP, Devi LA, Rozenfeld R.
Abstract:
The major cellular event in the development and progression of liver
fibrosis is the activation of hepatic stellate cells (HSCs). Activated
HSCs proliferate and produce excess collagen, leading to accumulation of
scar matrix and fibrotic liver. As such, the induction of activated HSC
death has been proposed as a means to achieve resolution of liver
fibrosis. Here we demonstrate that cannabidiol (CBD), a major
non-psychoactive component of the plant Cannabis sativa, induces
apoptosis in activated HSCs through a cannabinoid receptor-independent
mechanism. CBD elicits an endoplasmic reticulum (ER) stress response,
characterized by changes in ER morphology and the initiation of
RNA-dependent protein kinase-like ER kinase-, activating transcription
factor-6-, and inositol-requiring ER-to-nucleus signal kinase-1
(IRE1)-mediated signaling cascades. Furthermore, CBD induces downstream
activation of the pro-apoptotic IRE1/ASK1/c-Jun N-terminal kinase
pathway, leading to HSC death. Importantly, we show that this mechanism
of CBD-induced ER stress-mediated apoptosis is specific to activated
HSCs, as it occurs in activated human and rat HSC lines, and in primary
in vivo-activated mouse HSCs, but not in quiescent HSCs or primary
hepatocytes from rat. Finally, we provide evidence that the elevated
basal level of ER stress in activated HSCs has a role in their
susceptibility to the pro-apoptotic effect of CBD. We propose that CBD,
by selectively inducing death of activated HSCs, represents a potential
therapeutic agent for the treatment of liver fibrosis.