Search

Biliary fibrosis is the driving pathological process in cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Cholangiopathies are also associated with cholestasis, which is the retention of biliary components, including bile acids, in the liver and blood. Cholestasis may worsen with biliary fibrosis. Furthermore, bile acid levels, composition and homeostasis are dysregulated in PBC and PSC. In fact, mounting data from animal models and human cholangiopathies suggest that bile acids play a crucial role in the pathogenesis and progression of biliary fibrosis. The identification of bile acid receptors has advanced our understanding of various signaling pathways involved in regulating cholangiocyte functions and the potential impact on biliary fibrosis. We will also briefly review recent findings linking these receptors with epigenetic regulatory mechanisms. Further detailed understanding of bile acid signaling in the pathogenesis of biliary fibrosis will uncover additional therapeutic avenues for cholangiopathies.

Liver cancer is the second leading cause of cancer-related death globally, with limited treatment options. Recent studies have demonstrated the critical role of long noncoding RNAs (lncRNAs) in the pathogenesis of liver cancers. Of note, mounting evidence has shown that lncRNA H19, an endogenous noncoding single-stranded RNA, functions as an oncogene in the development and progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumors in adults. H19 can affect many critical biological processes, including the cell proliferation, apoptosis, invasion, and metastasis of liver cancer by its function on epigenetic modification, H19/miR-675 axis, miRNAs sponge, drug resistance, and its regulation of downstream pathways. In this review, we will focus on the most relevant molecular mechanisms of action and regulation of H19 in the development and pathophysiology of HCC and CCA. This review aims to provide valuable perspectives and translational applications of H19 as a potential diagnostic marker and therapeutic target for liver cancer disease.

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.

Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C−C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases.

Sipunculus nudus, an old marine species, has great potential for use as functional seafood due to its various bioactivities. Its potential antithrombotic activity pushed us to isolate the bio-active components bio-guided by tracking fibrinolytic activity. As a result, a novel protease named as SK (the kinase obtained from S. nudus) was obtained, which possessed a molecular weight of 28,003.67 Da and 15 N-terminal amino acid sequences of PFPVPDPFVWDTSFQ. SK exerted inhibitory effects on thrombus formation through improving the coagulation system with dose-effect relationship within a certain range. Furthermore, in most cases SK got obviously better effect than that of urokinase. With the help of untargeted mass spectrometry-based metabolomics profiling, arachidonic acid, sphingolipid, and nicotinate and nicotinamide mechanism pathways were found to be important pathways. They revealed that the effect mechanism of SK on common carotid arterial thrombosis induced by FeCl3 was achieved by inhibiting vessel contraction, platelet aggregation, adhesion, and release, correcting endothelial cell dysfunction and retarding process of thrombus formation. This study demonstrated SK was a promising thrombolytic agent on the basis of its comprehensive activities on thrombosis, and it should get further exploitation and utilization.