Therapeutic modulation of the bile acid pool by Cyp8b1 knockdown protects against nonalcoholic fatty liver disease in mice

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Raphael ChevreRoshni R Singaraja

Abstract

Bile acids (BAs) are surfactant molecules that regulate the intestinal absorption of lipids. Thus, the modulation of BAs represents a potential therapy for nonalcoholic fatty liver disease (NAFLD), which is characterized by hepatic accumulation of fat and is a major cause of liver disease worldwide. Cyp8b1 is a critical modulator of the hydrophobicity index of the BA pool. As a therapeutic proof of concept, we aimed to determine the impact of Cyp8b1 inhibition in vivo on BA pool composition and as protection against NAFLD. Inhibition of Cyp8b1 expression in mice led to a remodeling of the BA pool, which altered its signaling properties and decreased intestinal fat absorption. In a model of cholesterol-induced NAFLD, Cyp8b1 knockdown significantly decreased steatosis and hepatic lipid content, which has been associated with an increase in fecal lipid and BA excretion. Moreover, inhibition of Cyp8b1 not only decreased hepatic lipid accumulation, but also resulted in the clearance of previously accumulated hepatic cholesterol, which led to a regression in hepatic steatosis. Taken together, our data demonstrate that Cyp8b1 inhibition is a viable therapeutic target of crucial interest for metabolic diseases, such as NAFLD.-Chevre, R...Continue Reading

References

May 21, 1999·Science·M MakishimaB Shan
May 21, 1999·Science·D J ParksJ M Lehmann
Jun 9, 1999·Molecular Cell·H WangB M Forman
Nov 7, 2002·Biochemical and Biophysical Research Communications·Takaharu MaruyamaKenichi Tanaka
Jan 14, 2003·The Journal of Biological Chemistry·Yuji KawamataMasahiko Fujino
May 16, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·David Q-H WangMartin C Carey
Aug 28, 2007·Journal of Lipid Research·Insook KimFrank J Gonzalez
Feb 19, 2008·Thyroid : Official Journal of the American Thyroid Association·Charles ThomasKristina Schoonjans
Jun 13, 2008·Nature Protocols·Thomas D Schmittgen, Kenneth J Livak
Aug 2, 2008·Nature Reviews. Drug Discovery·Charles ThomasKristina Schoonjans
Oct 16, 2008·Current Gene Therapy·Benoit BarteauBruno Pitard
Oct 29, 2008·Seminars in Liver Disease·Mariana Lazo, Jeanne M Clark
Jan 8, 2009·Physiological Reviews·Philippe LefebvreBart Staels
Apr 7, 2009·Journal of Lipid Research·Phillip B HylemonPaul Dent
Sep 3, 2009·Cell Metabolism·Charles ThomasKristina Schoonjans
Mar 26, 2010·Scandinavian Journal of Gastroenterology·Antal BajorHasse Abrahamsson
May 13, 2010·Digestive Diseases·Michael TraunerMartin Wagner
Aug 3, 2010·Journal of Lipid Research·Katharina SlätisGösta Eggertsen
Dec 22, 2011·Current Opinion in Lipidology·Carolien OutGemma Brufau
May 3, 2012·Journal of Lipid Research·Geoffrey PorezBart Staels
May 24, 2012·Current Opinion in Lipidology·Anthony S Wierzbicki, Jude Oben
Feb 19, 2013·Journal of Lipid Research·George N IoannouChristopher Savard
Aug 29, 2013·Nature Reviews. Gastroenterology & Hepatology·Frank G SchaapPeter L M Jansen
Oct 24, 2014·Diabetes·Achint KaurMichael R Hayden
Nov 18, 2014·World Journal of Gastroenterology : WJG·Petros Zezos, Eberhard L Renner
Aug 19, 2015·Nature Reviews. Genetics·Anders Wittrup, Judy Lieberman
Nov 12, 2015·Journal of Hepatology·Akiko EguchiAriel E Feldstein
Dec 17, 2015·World Journal of Hepatology·Liyun Yuan, Kiran Bambha
Dec 14, 2016·The New England Journal of Medicine·Kevin FitzgeraldAmy Simon
Apr 6, 2017·American Journal of Physiology. Endocrinology and Metabolism·Enrico BertaggiaRebecca A Haeusler
Jul 12, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Puneet PuriArun J Sanyal

❮ Previous
Next ❯

Citations

Nov 23, 2018·Biological Chemistry·Linbing FanMatthias Bureik
Jan 28, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·John Y L Chiang, Jessica M Ferrell
Jun 19, 2019·Diabetes & Metabolism Journal·Jessica M Ferrell, John Y L Chiang
Jul 22, 2020·The Journal of Biological Chemistry·Tiara R AhmadRebecca A Haeusler
May 19, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Joanne A HoogerlandMaaike H Oosterveer
Sep 10, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Yunxia Yang, Jianfa Zhang
Oct 13, 2019·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yanyong XuYanqiao Zhang
Aug 14, 2020·Physiological Reviews·Alessia PerinoKristina Schoonjans
Jul 23, 2021·Liver Research·John Y L Chiang, Jessica M Ferrell

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.