TY - JOUR
T1 - Bile acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet-fed mice
AU - Takahashi, Shogo
AU - Luo, Yuhuan
AU - Ranjit, Suman
AU - Xie, Cen
AU - Libby, Andrew E.
AU - Orlicky, David J.
AU - Dvornikov, Alexander
AU - Wang, Xiaoxin X.
AU - Myakala, Komuraiah
AU - Jones, Bryce A.
AU - Bhasin, Kanchan
AU - Wang, Dong
AU - McManaman, James L.
AU - Krausz, Kristopher W.
AU - Gratton, Enrico
AU - Ir, Diana
AU - Robertson, Charles E.
AU - Frank, Daniel N.
AU - Gonzalez, Frank J.
AU - Levi, Moshe
AU - Pessin, Jeffrey E.
N1 - Funding Information:
This work was supported by National Institute of Aging Grant AG049493 (to M. L.), National Institute of Diabetes and Digestive and Kidney Dis-eases Grant 116567 (to M. L.), National Institutes of Health Grants 2R01HD45965 and R01-HD075285 (to J. L. M.), Colorado Clinical and Translational Sciences Institute/National Institutes of Health Grant TL1-TR001081 (to A. E. L.), and National Institutes of Health Grants P50GM076516 and P41GM103540 (to S. R., A. D., and E. G.). This work was also supported by funds from the Gastrointestinal and Liver Innate Immunity Program of the University of Colorado School of Medicine (to D. N. F., D. I., and C. E. R.) and American Heart Association Postdoctoral Fellowships 19POST34430001 (to A. E. L.) and 19POST34381041 (to K. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
PY - 2020/4/3
Y1 - 2020/4/3
N2 - Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal bile acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of bile acids can greatly disrupt metabolic homeostasis. Bile acid sequestrants are orally administered polymers that bind bile acids in the intestine, forming nonabsorbable complexes. Bile acid sequestrants interrupt intestinal reabsorption of bile acids, decreasing their circulating levels. We determined that treatment with the bile acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio. The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
AB - Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal bile acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of bile acids can greatly disrupt metabolic homeostasis. Bile acid sequestrants are orally administered polymers that bind bile acids in the intestine, forming nonabsorbable complexes. Bile acid sequestrants interrupt intestinal reabsorption of bile acids, decreasing their circulating levels. We determined that treatment with the bile acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio. The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
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U2 - 10.1074/jbc.RA119.011913
DO - 10.1074/jbc.RA119.011913
M3 - Article
C2 - 32075905
AN - SCOPUS:85082971384
VL - 295
SP - 4733
EP - 4747
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 14
ER -