Bile acids as drivers and biomarkers of hepatocellular carcinoma

Abstract

The prevalence of hepatocellular carcinoma (HCC) is rapidly increasing, driven not least in part by the escalating prevalence of non-alcoholic fatty liver disease. Bile acid (BA) profiles are altered in patients with HCC and there is a developing body of evidence from in vitro human cellular models as well as rodent data suggesting that BA are able to modulate fundamental processes that impact on cellular phenotype predisposing to the development of HCC including senescence, proliferation and epithelial-mesenchymal transition. Changes in BA profiles associated with HCC have the potential to be exploited clinically. Whilst excellent diagnostic and imaging tools are available, their use to screen populations with advanced liver disease at risk of HCC is limited by high cost and low availability. The mainstay for HCC screening among subjects with cirrhosis remains frequent interval ultrasound scanning. Importantly, currently available serum biomarkers add little to diagnostic accuracy. Here, we review the current literature on the use of BA measurements as predictors of HCC incidence in addition to their use as a potential screening method for the early detection of HCC. Whilst these approaches do show early promise, there are limitations including the relatively small cohort sizes, the lack of a standardized approach to BA measurement, and the use of inappropriate control comparator samples.

Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor–deficient mice

“…FXR deficiency results in altered bile acid metabolism marked with an overproduction of bile acids in the liver and their diminished transport into the gallbladder. Evidence of bile acids as a potential hepatic carcinogen 6 supported the next step to measure a large panel of bile acid biosynthesis, feedback regulators, and transporters at both major sites of FXR signaling, the liver and ileum. We first analyzed the expression of genes associated with the classical and alternative pathways of bile acid biosynthesis in the liver.…”

“…It is likely due in part to bile acid-mediated inflammation resulting in fibrosis and cirrhosis that could lead to hepatocarcinogenesis. 6 …”

Alteration of serum bile acid profiles of HBV-related hepatocellular carcinoma identified by LC–MS/MS

“…As the final products of cholesterol catabolism, bile acids are essential for the absorption, transport, and metabolism of lipids (Li and Chiang 2014 ). Furthermore, bile acids have a diverse array of functions to regulate cellular metabolic, inflammatory, and proliferative phenotypes (Colosimo and Tomlinson 2022 ). An important determinant of the biological effects of bile acids is their ability to activate a variety of receptors and mediate downstream signals.…”

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma

“…A collaborative action of different BAs, all characterised by high hydrophobicity, has been observed in downregulating tumour suppressor genes like CEBPα, thereby helping the development of liver cancer [38]. Altered BA levels, besides leading to metabolic dysfunction [39], can induce senescence, resistance to apoptosis, and hyper-proliferation [40], all hallmarks of the neoplastic transition. BAs can exert a significant cytotoxic effect when they accumulate inside the liver at high concentrations because of their direct cytolytic action [41].…”