Liver X Receptor α–Induced Cannabinoid Receptor 2 Inhibits Ubiquitin‐Specific Peptidase 4 Through miR‐27b, Protecting Hepatocytes From TGF‐β

Abstract

Liver X receptor‐alpha (LXRα) acts as a double‐edged sword in different biological situations. Given the elusive role of LXRα in hepatocyte viability, this study investigated whether LXRα protects hepatocytes from injurious stimuli and the underlying basis. LXRα activation prevented hepatocyte apoptosis from CCl4 challenges in mice. Consistently, LXRα protected hepatocytes specifically from transforming growth factor‐beta (TGF‐β), whereas LXRα deficiency aggravated TGF‐β‐induced hepatocyte injury. In the Gene Expression Omnibus database analysis for LXR−/− mice, TGF‐β receptors were placed in the core network. Hierarchical clustering and correlation analyses enabled us to find cannabinoid receptor 2 (CB2) as a gene relevant to LXRα. In human fibrotic liver samples, both LXRα and CB2 were lower in patients with septal fibrosis and cirrhosis than those with portal fibrosis. LXRα transcriptionally induced CB2; CB2 then defended hepatocytes from TGF‐β. In a macrophage depletion model, JWH133 (a CB2 agonist) treatment prevented toxicant‐induced liver injury. MicroRNA 27b (miR‐27b) was identified as an inhibitor of ubiquitin‐specific peptidase 4 (USP4), deubiquitylating TGF‐β receptor 1 (TβRI), downstream from CB2. Liver‐specific overexpression of LXRα protected hepatocytes from injurious stimuli and attenuated hepatic inflammation and fibrosis. Conclusion: LXRα exerts a cytoprotective effect against TGF‐β by transcriptionally regulating the CB2 gene in hepatocytes, and CB2 then inhibits USP4‐stabilizing TβRI through miR‐27b. Our data provide targets for the treatment of acute liver injury.

Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist

“…Cumulatively, CB2R stimulation decreased liver fibrosis by specifically decreasing IL-17 production by Th17 lymphocytes in a STAT5-dependent manner and decreasing the proinflammatory activity of IL-17 while conserving IL-22 production. Wu et al (2019) found that treating mice with JWH133 and CCL4 plus clodronate inhibited toxicant-mediated hepatic injury, as demonstrated by reduced levels of ALT, AST, apoptotic cells, caspase-3, and CREB. JWH133 also attenuated protein kinase A activity except in CB2-deficient mice, demonstrating that hepatocytic cells express functionally active CB2 downstream of the liver X receptors (LXRα).…”

“…Comparing with another natural cannabinoid with high selectivity to CB2R, β-caryophyllene (BCP), which selectively and competitively interact with the CP55,940 binding site (i.e., THC binding site) of the CB2R, with 165-fold selectivity over CB1R, where it showed a weak partial agonism (Gertsch et al, 2008). JWH133 exhibits anticancer (Sánchez et al, 2001;Qamri et al, 2009), cardioprotective (Yu et al, 2019), hepatoprotective (Wu et al, 2019), gastroprotective (Tartakover Matalon et al, 2020), nephroprotective (Feizi et al, 2008), anti-inflammatory (Çakır et al, 2020), antihyperalgesic (Cabañero et al, 2020), and immunomodulatory activities (Zhu et al, 2019). It has also been demonstrated to exert neuroprotective effects in Parkinson's disease, ischemic stroke, depression, anxiety, Alzheimer's disease, epilepsy, and neuropathic pain (Kruk-Slomka et al, 2015;Sheng et al, 2019;Cao et al, 2020;Ivy et al, 2020;Jia et al, 2020;Jing et al, 2020;Zhao et al, 2020).…”

Phytocannabinoids—A Green Approach toward Non-Alcoholic Fatty Liver Disease Treatment

“…Considering it in the liver, CB2R was identified mainly in Kupffer cells and stellate cells, and it is up regulated during pathology, especially occurring with inflammation such as NASH. However, the expression of this receptor in healthy hepatocytes is weak [30]. Although CBRs were believed to be functional only at plasma membranes, it is currently known that they are also expressed in intracellular organelle, e.g., mitochondria, where their role is not fully understood [31].…”

Hypergravity Load Modulates Acetaminophen Nephrotoxicity via Endoplasmic Reticulum Stress in Association with Hepatic microRNA-122 Expression

“…Upon slicing the kidney samples, the tissue slices were fixed in 10% buffered-neutral formalin for 6 h. The samples were then stained with H&E, as previously described [ 43 ].…”