Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease

Abstract

Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.

Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

“…As an intrahepatic factor, the biliary compartment is increasingly recognized as a potential driver of inflammation in NAFLD (Figure 1) [51]. Patients with progressive NAFLD frequently show biliary epithelial cell proliferation and a so-called "ductular reaction" that correlated with portal inflammation, NASH activity and fibrosis [52].…”

“…Patients with progressive NAFLD frequently show biliary epithelial cell proliferation and a so-called "ductular reaction" that correlated with portal inflammation, NASH activity and fibrosis [52]. Ductular reaction refers to histological J o u r n a l P r e -p r o o f biliary cell proliferation or hyperplasia and is rooted either in proliferation of cholangiocytes, hepatic progenitor cells or transdifferentiation of hepatocytes to cholangiocytes, which is still a topic of debate [51]. Furthermore, NASH patients with cholestasis had more advanced histological disease compared to age-and sex-matched controls without cholestasis [53].…”

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

“…Senescence has been the focus of recent studies with respect to various metabolic conditions including NAFLD (Zhou et al, 2021). Senescence, independent of aging, can exacerbate disease phenotypes resulting in the progression of the metabolic condition.…”

“…The role of hepatocytes has been well studied in NAFLD (Venkatesh et al, 2017;Simon et al, 2020); however, there has been increasing interest in the contribution from cholangiocytes (Mendez-Sanchez et al, 2007;Kennedy et al, 2021;Zhou et al, 2021). A study showing evidence of DR in NAFLD was performed in rats fed with choline deficient high trans-fat diet where severe hepatic injuries were identified in areas of liver section with more CK-19 positive DR as identified by immunohistochemistry (de Lima et al, 2008).…”

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

“…The disease ranges from mild steatosis (non-alcoholic fatty liver, NAFL) to severe steatosis with inflammation and fibrosis (non-alcoholic steatohepatitis, NASH) [ 2 ]. Failure of the parenchymal hepatocytes to cope with the chronically high lipid load is a critical event in NAFLD pathology, and the consequential lipotoxicity triggers a cascade of pathogenic events in the non-parenchymal cell populations such as the activation of Kupffer cells (KCs), immune cell infiltration, liver sinusoidal endothelial cell (LSEC) capillarization, hepatic stellate cell (HSC) activation, and epithelial ductular reaction comprising activation, proliferation, and potential transdifferentiation amongst cholangiocytes, bipotent biliary progenitor cells or hepatocytes, or a combination of these [ 2 , 4 , 5 , 6 , 7 , 8 ]. This causes dramatic alterations of tissue architecture and function that ultimately may lead to NASH and can result in cirrhosis and liver failure [ 2 , 9 ].…”