Hepatic Autophagy Deficiency Compromises Farnesoid X Receptor Functionality and Causes Cholestatic Injury.

Abstract

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury.

• Authors: Bilon Khambu, Tiangang Li, Shengmin Yan, Changshun Yu, Xiaoyun Chen, Michael Goheen, Yong Li, Jingmei Lin, Oscar W Cummings, Youngmin A Lee, Scott Friedman, Zheng Dong, Gen-Sheng Feng, Shangwei Wu, Xiao-Ming Yin
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 69 Issue 5 Pg. 2196-2213 (05 2019) ISSN: 1527-3350 [Electronic] United States
• PMID: 30520052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2018 by the American Association for the Study of Liver Diseases.

Chemical References

• Bile Acids and Salts
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Receptors, Cytoplasmic and Nuclear
• farnesoid X-activated receptor

Topics

• Animals
• Autophagy
• Bile Acids and Salts (blood)
• Cholestasis, Intrahepatic (etiology, metabolism)
• Female
• Food Deprivation
• Liver (ultrastructure)
• Male
• Mice, Transgenic
• NF-E2-Related Factor 2 (metabolism)
• Receptors, Cytoplasmic and Nuclear (metabolism)