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Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients
Author(s) -
Mueller Michaela,
Castro Rui E.,
Thorell Anders,
Marschall HannsUlrich,
Auer Nicole,
Herac Merima,
Rodrigues Cecilia M.P.,
Trauner Michael
Publication year - 2018
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13562
Subject(s) - ursodeoxycholic acid , unfolded protein response , oxidative stress , medicine , steatosis , endocrinology , chop , apoptosis , gastroenterology , pharmacology , chemistry , biochemistry , chemotherapy
Background & Aims Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid (BA) used as therapy for a range of hepatobiliary diseases. Its efficacy in non‐alcoholic fatty liver disease (NAFLD) is still under debate. Here, we aimed to decipher molecular mechanisms of UDCA in regulating endoplasmic reticulum (ER) homeostasis, apoptosis and oxidative stress in morbidly obese patients. Methods In this randomized controlled pharmacodynamic study, liver and serum samples from 40 well‐matched morbidly obese NAFLD‐patients were analysed. Patients received UDCA (20 mg/kg/d) or no treatment 3 weeks before samples were obtained during bariatric surgery. Results Patients treated with UDCA displayed higher scoring of steatosis (S), activity (A) and fibrosis (F), the so called SAF‐scoring. UDCA partially disrupted ER homeostasis by inducing the expression of the ER stress markers CHOP and GRP78 . However, ERDJ4 and sXBP1 levels were unaffected. Enhanced CHOP expression, a suggested pro‐apoptotic trigger, failed to induce apoptosis via BAK and BAX in the UDCA treated group. Potentially pro‐apoptotic miR‐34a was reduced in the vesicle‐free fraction in serum but not in liver after UDCA treatment. Thiobarbituric acid reactive substances, 4‐hydroxynonenal and mRNA levels of several oxidative stress indicators remained unchanged after UDCA treatment. Conclusion Our data suggest that UDCA treatment has ambivalent effects in NAFLD patients. While increased SAF‐scores and elevated CHOP levels may be disadvantageous in the UDCA treated cohort, UDCA's cytoprotective properties potentially changed the apoptotic threshold as reflected by absent induction of pro‐apoptotic triggers. UDCA treatment failed to improve the oxidative stress status in NAFLD patients.