Endocannabinoids in liver disease

Abstract

Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB 1 receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB 1 blockade. In mouse models of liver fibrosis, the activation of CB 1 receptors on hepatic stellate cells is fibrogenic, and CB 1 blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB 1 receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB 1 blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB 1 antagonists. (HE-PATOLOGY 2011;53:346-355)

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

“…16,39,41 There is a general consensus that the EC system is activated during cirrhosis. 4,5,[44][45][46][47][48] Accordingly, our untreated cirrhotic rats had a significant upregulation of CB1 and CB2 receptors along fibrotic septa and portal tracts where maximal is the presence of activated HSC expressing the CB receptors, as reported by other authors in rats and humans. 4,5,[45][46][47] Furthermore, the downregulation of the enzymes responsible for EC degradation, FAAH and MAGL, represents indirect evidence of increased hepatic EC levels in cirrhotic livers.…”

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

“…Hepatic inflammation and fibrosis were remarkably ameliorated by blocking CB1. An increasing body of evidence has shown the changes of ECS in various liver injuries (32). For example, Mallat and Lotersztajn (33) reported the rising levels of endocannabinoids during liver injury and fibrogenesis.…”

“…The comprehensive changes of four primary enzymes and two receptors indicate the importance of ECS. These elevated endocannabinoids and their receptors play different roles in liver diseases through connecting with multiple cells, including macrophages (32).…”

Hepatorenal Syndrome-Current Concepts in Pathophysiology

“…Production of NO by activation of eNOS plays a major role in splanchnic and systemic vasodilation, however increased inducible NOS activity and neuronal NOS production has also been demonstrated [20][21][22]. Together with NO, prostacyclin (PGI2) [23][24][25], carbon monoxide (CO) [26,27], various other vasodilators like endocannabinoids [28], hydrogen sulfide [29] etc also play a role in splanchnic and systemic vasodilation. As a consequence of splanchnic and systemic vasodilation, effective arterial volume decreases and to compensate arterial hypovolemia, cardiac output increases setting in a hyperdynamic state.…”