Dysregulation of Bile Acids in Patients with NAFLD

Abstract

Bile acids are synthesized in the liver and tightly regulated through the enterohepatic circulation. Recent studies reveal that bile acids serve as hormone-like signaling molecules to activate nuclear receptors, notably farnesoid X receptor (FXR), regulating metabolic homeostasis of bile acids, cholesterol, lipids, and glucose. A connection between bile acids and nonalcoholic fatty liver disease (NAFLD) has long been recognized. Although inconsistent or even contradictory results are reported, a large body of evidence from clinical as well as preclinical studies demonstrates that bile acid homeostasis is disrupted in patients with NAFLD. The bile acid dysregulation gets worsening as NAFLD progresses from early stage simple steatosis to late stage nonalcoholic steatohepatitis (NASH) and NASH with fibrosis. As the risk factors for NAFLD, obesity and insulin resistance, which are often associated with NAFLD, contribute to the dysregulation of bile acids in patients with NAFLD. Total serum and fecal bile acid concentrations are mostly elevated in patients with NAFLD as a result of increased bile acid synthesis, elevated hepatic bile acids, and upregulation of bile acid transporters. The two negative feedback regulatory pathways for bile acid synthesis, FXR/SHP (small heterodimer partner) and fibroblast growth factor-19 (FGF19)/FGF receptor-4 (FGFR4), are impaired in patients with NAFLD.

Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus

“…In healthy liver, BA metabolism is tightly regulated through enterohepatic circulation of BAs, and BA homeostasis is maintained through multiple negative feedback mechanisms, such as farnesoid X receptor (FXR)/small heterodimer partner (SHP) and FGF19/FGF receptor‐4 (FGFR4) signalling 37,38 . A growing body of literature has reported that the levels of total and primary BAs are elevated in the serum, plasma, stool and liver of patients with NAFLD, implying an association between BA metabolism and the pathogenesis of NASH 1,7 .…”

ID1-Mediated BMP Signaling Pathway Potentiates Glucagon-Like Peptide-1 Secretion in Response to Nutrient Replenishment

“…Therefore, it is plausible that enhancement of cAMP signaling may potentiate BMP signaling pathway to potentiate GLP-1 secretion. It has also been reported that dysregulation of bile acid signaling became worse in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [32]. Moreover, NAFLD and NASH patients have been reported to have deficiency in glucose-stimulated GLP-1 secretion [33].…”

A microfluidic patterned model of non-alcoholic fatty liver disease: applications to disease progression and zonation

“…MRP3 contributes to the transport of biliary excretion and was shown to get upregulated in both expression and activity in NAFLD patients as well as animal models. 47,48 In mice with hepatic steatosis, the mRNA levels of MRP3 increased by 3.3fold, compared to wild-type animals. 49 Comparable to these results, we observed an increase of up-to 3.4-fold in MRP3 expression levels in rat primary hepatocytes.…”