Many receptors can be activated by bile acids (BAs) and their derivatives. These include nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), as well as membrane receptors Takeda G protein receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cholinergic receptor muscarinic 2 (CHRM2). All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure. Because epigenetic regulation is critical for organisms to adapt to constant environmental changes, this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid receptors. In addition, the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs. Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.

Many receptors can be activated by bile acids (BAs) and their derivatives. These include nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), as well as membrane receptors Takeda G protein receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cholinergic receptor muscarinic 2 (CHRM2). All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure. Because epigenetic regulation is critical for organisms to adapt to constant environmental changes, this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid receptors. In addition, the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs. Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.

Over the past decade, many studies have revealed the importance of the gut microbiome in disease development and treatment, including in cancer. Because both host genetics and the gut microbiome can influence host phenotype and treatment outcome, there is an urgent need to develop precision medicine and personalize dietary supplementation based on an individual’s microbiome.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a low survival rate. The identification of mechanisms underlying the development of HCC helps uncover cellular and molecular targets for the diagnosis, prevention, and treatment of HCC. Golgi protein 73 (GP73) level is upregulated in HCC patients and potentially can be a therapeutic target. Despite many studies devoted to GP73 as a marker for HCC early diagnosis, there is little discussion about the function of GP73 in HCC tumorigenesis. Given the poor response to currently available HCC therapies, a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC. The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis. Its roles in other types of cancer are also discussed.

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.

Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.

Background

Retinoids are used to treat several types of cancer; however, their effects on liver cancer have not been fully characterized. To investigate the therapeutic potential of retinoids on hepatocellular carcinoma (HCC), the present study evaluates the apoptotic effect of a panel of natural and synthetic retinoids in three human HCC cell lines as well as explores the underlying mechanisms.

Methods

Apoptosis was determined by caspase-3 cleavage using western blot, DNA double-strand breaks using TUNEL assay, and phosphatidylserine translocation using flow cytometry analysis. Gene expression of nuclear receptors was assessed by real-time PCR. Transactivation assay and chromatin immunoprecipitation (ChIP) were conducted to evaluate the activation of RXRalpha/RARbeta pathway by fenretinide. Knockdown of RARbeta mRNA expression was achieved by siRNA transfection.

Results

Our data revealed that fenretinide effectively induces apoptosis in Huh-7 and Hep3B cells. Gene expression analysis of nuclear receptors revealed that the basal and inducibility of retinoic acid receptor beta (RARbeta) expression positively correlate with the susceptibility of HCC cells to fenretinide treatment. Furthermore, fenretinide transactivates the RXRalpha/RARbeta-mediated pathway and directly increases the transcriptional activity of RARbeta. Knockdown of RARbeta mRNA expression significantly impairs fenretinide-induced apoptosis in Huh-7 cells.

Conclusion

Our findings reveal that endogenous expression of retinoids receptor RARbeta gene determines the susceptibility of HCC cells to fenretinide-induced apoptosis. Our results also demonstrate fenretinide directly activates RARbeta and induces apoptosis in Huh-7 cells in a RARbeta-dependent manner. These findings suggest a novel role of RARbeta as a tumor suppressor by mediating the signals of certain chemotherapeutic agents.

It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRalpha on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARalpha agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66 +/- 10%. This effect was essentially absent (13 +/- 8%) in hepatocyte-specific RXRalpha-deficient mice. Similarly, pretreatment of WT mice with the PPARdelta agonist L-783483 or the PPARgamma agonist L-805645 caused 54 +/- 1% and 38 +/- 8% reduction in carrageenan-induced paw edema, respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRalpha-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRalpha-deficient mice. The identification of RXRalpha as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.

Liver cancer is the sixth most common cancer worldwide, and the third most common cause of cancer-related death. Hepatocellular carcinoma (HCC), which accounts for more than 90% of primary liver cancers, is an important public health problem. In addition to cirrhosis caused by hepatitis B viral (HBV) or hepatitis C viral (HCV) infection, non-alcoholic fatty liver disease (NAFLD) is becoming a major risk factor for liver cancer because of the prevalence of obesity. Non-alcoholic steatohepatitis (NASH) will likely become the leading indication for liver transplantation in the future. It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer. The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies. In this article, we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.