Non-alcoholic fatty liver disease (NAFLD), cirrhosis, and liver cancer stand as prevalent clinical liver ailments posing substantial threats to individuals' well-being and lives. G protein-coupled receptors (GPCRs), the largest recognized superfamily of cell surface receptors, constitute approximately 2% of the total protein count encoded by the human genome. Intriguingly, about 34% of sanctioned pharmaceuticals exert their effects by modulating GPCRs to either activate or inhibit intricate signal transduction cascades. Notably, research has underscored the involvement of specific GPCRs in governing energy and liver metabolism through their binding with hormone receptors, including receptors for glucagon, adrenaline, cannabinoids, and angiotensin, all of which can be found within the liver. Intervening in these receptors and their associated signaling pathways holds promise in rectifying liver metabolic dysfunctions and related maladies.
The Role of GPCR in Liver Disease
Aberrations in GPCR have been linked to a spectrum of conditions, including liver diseases, rendering GPCRs an appealing focus of therapeutic attention in recent times.
Role of GPCRs and Their Receptors in the Occurrence and Development of NAFLD
The prevalence of NAFLD is on the rise, emerging as a prominent culprit behind persistent liver ailments, affecting approximately 6% of the global populace. Despite its widespread impact, there are currently no authorized medications tailored to combat this disease. Notably, NAFLD is intricately entwined with metabolic syndrome, showcasing a distinct hallmark of excessive lipid buildup within the liver. This condition often escalates into non-alcoholic steatohepatitis (NASH), characterized by liver steatosis, heightened oxidative stress, inflammation, and injury to liver cells, occasionally accompanied by fibrosis. Noteworthy studies have unveiled the potential utilization of GPCR agonists or antagonists in tackling metabolic disorders, thereby propelling advancements in GPCR-targeted therapies for NASH.
Role of GPCRs and Their Receptors in the Occurrence and Development of Liver Cirrhosis
In the realm of liver health, the emergence and progression of liver cirrhosis often stem from the widespread occurrence of liver fibrosis, ultimately leading to liver failure and the emergence of hepatocellular carcinoma. Notably, the primary culprits behind liver cirrhosis encompass HBV and HCV infections, alcoholic hepatitis, as well as NAFLD, among a myriad of other potential factors. Recent years have witnessed an upsurge in the exploration of GPCRs, unveiling their intricate involvement in the genesis and advancement of liver fibrosis.
Within the realm of GPCRs, the spotlight often falls on cannabinoid receptors (CBRs), comprising the CB1 and CB2 receptors nestled within the expansive GPCR family. These receptors adeptly mediate the biological impacts triggered by both plant-derived and endogenous cannabinoids. Delving deeper into research, it becomes evident that CB2 receptors hold a pivotal position in governing acute and chronic liver injuries, while also exerting a considerable influence on the trajectory of liver fibrosis, ischemia-reperfusion-induced liver injury, and liver encephalopathy.
Additionally, succinate, a crucial intermediate product of the tricarboxylic acid cycle, assumes a central role in the generation of mitochondrial ATP. However, its significance goes beyond mere energy production, as it also wields a profound impact on a spectrum of biological processes, including epigenetics, signal transduction, inflammation, tumor initiation, and paracrine modulation of various organs such as the kidneys, retina, heart, immune tissues, and liver. The GPCR91, identified as a succinate receptor, surfaces as a key player in the intricate cascade of events. Notably, the accumulation of succinate within liver cells triggers the activation of HSCs, orchestrating a crucial step in the complex trajectory of liver fibrosis. Consequently, strategies aimed at curtailing succinate accumulation may offer a promising avenue to reverse liver fibrosis by regulating the survival and proliferation of HSCs.
Role of GPCRs and Their Receptors in the Occurrence and Development of Liver Cancer
Hepatocellular carcinoma (HCC) accounts for about 90% of all liver cancer cases. Previous studies have shown that GPCR-mediated signaling pathways are key regulators of oncogenes. In recent years, studies have found that GPCRs are closely related to the occurrence and metastasis of tumors, especially in GPCRs associated with chemokines, prostaglandins, lysophosphatidic acid, endothelins, catecholamines, and angiotensin, playing an important role in liver cancer cell proliferation, invasion, metastasis, and angiogenesis. Interfering with GPCRs and their downstream signaling targets can help identify potential targets for the treatment of liver cancer.
Lysophosphatidic acid (LPA) represents a bioactive lipid regulator wielding diverse physiological and pathological roles across various cell types. Its impact unfolds through interaction with multiple subtypes (LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6) of the endothelial differentiation gene (Edg) family of GPCRs, thereby inciting a cascade of biological responses. Notably, investigations have underscored the escalated presence of LPAR6 within liver cancer cells, with evidence suggesting that different concentrations of LPA can elicit a dose-dependent escalation in the growth of these cells. Intervention targeting the LPA-LPAR signaling pathway has exhibited the potential to curb the rampant proliferation of liver cancer cells.
Furthermore, LPA-driven LPAR3 assumes a pivotal role in mediating tumor invasion through the ERK-MAPK signaling pathway. The intricate interplay between GPCRs and their ligands serves to propel the vascular invasion, proliferation, and migration of tumor cells.
In conclusion, more and more studies have shown that GPCR is closely related to the occurrence and progression of liver diseases such as NAFLD, liver fibrosis, cirrhosis, and hepatocellular carcinoma, and it is an interesting target for diagnosis and treatment.
References
- Yang M.; Zhang C. Y. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World Journal of Gastroenterology. 2021, 27(8): 677.
- Peng W. T.; et al. Emerging roles of G protein-coupled receptors in hepatocellular carcinoma. International Journal of Molecular Sciences. 2018, 19(5): 1366.
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