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Bile acids in nonalcoholic steatohepatitis: Pathophysiological driving force or innocent bystanders?

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases and is estimated to become the primary cause of liver transplantation within the next 20 years. The natural course of NAFLD starts with bland liver steatosis (nonalcoholic fatty liver; NAFL), which per se is a relatively benign state. However, NAFL can progress to nonalcoholic steatohepatitis (NASH), which is characterized by distinct histopathological changes including ballooning, inflammation, and fibrosis. Besides their function as intestinal “soaps” bile acids (BAs) act as specific signaling molecules regulating a broad range of metabolic pathways via activation of the BA receptors, farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. Whereas the pathophysiology of NAFLD is incompletely understood, several lines of evidence suggest an involvement of impaired BA homeostasis. This includes a general increase of total serum and fecal BA levels in NASH and a positive correlation of elevated total serum BAs with measures of disease severity (e.g., NAFLD activity). However, it is currently unclear whether and how BAs directly contribute to the pathomechanisms of NAFLD. In this issue of HEPATOLOGY, Puri et al. report that the presence and severity of NASH are associated with specific changes in serum BA composition. Using liquid chromatography/mass spectrometry–based relative quantification in a cohort of 62 NAFLD patients, the investigators show that the progression from NAFL to NASH is characterized by increased ratios of primary/secondary as well as conjugated/unconjugated BAs. More subtle analyses of individual primary BAs moreover suggest that NASH patients had an increased ratio of total (i.e., unconjugated, glycoconjugated, and tauro-conjugated) cholate (CA) to total chenodeoxycholate (CDCA) compared to either healthy controls (significant) or patients with NAFL (trend). In logistic regression models, certain CA conjugates were also positively correlated with the histological features of NASH, including steatosis (taurocholate; TCA), lobular inflammation (glycocholate; GCA), and ballooning (TCA), as well as with overall NAFLD activity (conjugated CA and TCA). Moreover, the abundance of conjugated CA was positively associated with an increased likelihood for significant liver fibrosis. Although it is currently unclear why BA composition is altered in NAFLD, it is equally intriguing to think about the putative downstream consequences of these alterations. In this regard, Puri et al. suggest that the gradual shift from CDCA to CA in NAFL and NASH may be accompanied by a reduction of FXR signaling attributed to the “dilution” of the potent Abbreviations: BA, bile acid; CA, cholic acid; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7 alpha-hydroxylase; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; GCA, glycocholate; GCDCA, glycochenodeoxycholate; MRP, multidrug resistance-associated protein; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NTCP, sodium-taurocholate cotransporting polypeptide; OCA, obeticholic acid; SHP, small heterodimer partner; TCA, taurocholate.