Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

Abstract

Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 were observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH.

Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

“…Consequently, hepatocellular damage is sustained throughout the progressive stages of NAFLD, leading to perturbations in gene regulation and liver function (Lake et al, 2011(Lake et al, , 2013. Among the many functions of the liver, it is a central mediator in governing the detoxification and elimination of both endo-and xenobiotics via a diverse array of biotransformation and transport mechanisms (Keogh, 2012).…”

Evaluation of the indicative roles of seven potential biomarkers on hepato-nephrotoxicity induced by Genkwa Flos

“…CA, as a better biochemical marker of hepatotoxicity in blood samples (Lu et al, 2013), was significantly elevated in the study after RGF-treated. Under the normal physiological condition, there was a small amount of CA in peripheral circulatory and the excessive excretion in serum may result from the poor reabsorption induced by hepatobiliary and intestinal disorders (Chiang, 2002).…”

“…Alterations in the BA profile may be the result of disease induced liver injury (Lake et al 2013). CA, one of the primary bile acids produced by liver, is widely recognized as a biomarker of hepatotoxicity (Geng et al, 2013a(Geng et al, , 2013b.…”

S2k-Leitlinie nicht alkoholische Fettlebererkrankungen

“…Der Schweregrad der hepatischen Entzündung steht in engem Zusammenhang mit dem Grad an Insulinresistenz [94]. Weiterhin zeigen sich Veränderungen des Leberzellstoffwechsels, einschließlich des Kortisol- [95] und des Gallensäuremetabolismus [96]. Bei der NASH kommt es zu Entzündungsprozessen in der Leber und im viszeralen Fettgewebe [97,98].…”