Bile; Cholestasis; Digestive System Diseases; Hepatitis; Jaundice; Liver; Cholangitis, Sclerosing
Our laboratory has a long standing interest in the basic physiology of bile formation and the pathophysiologic mechanisms underlying mechanisms of cholestasis. Bile formation is one of the unique functions of the liver and is impaired in many forms of cholestatic liver injury. Our early studies established that the hepatocyte is a polarized secretory cell where transport mechanisms are organized on plasma membrane domains like a classic epithelium (Physiologic Reviews 60:303-326, 1980). This concept has led to the identification and characterization of a number of membrane transport proteins both at the functional level and through molecular cloning techniques that determine the secretion of bile (Physiologic Reviews 83:633-671, 2003). Current studies focus on mechanisms by which bile acids injure the liver in cholestatic liver diseases and determinations of new approaches for therapy of these diseases including the use of biliary organoids and cell lines fro drug discovery. Trainees utilize a variety of fundamental techniques ranging from general cell biologic and molecular biologic procedures to advanced morphologic approaches including fluorescent and confocal scanning microscopy. This research is supported by NIH grants and core facilities provided by an NIH Liver Center.
Specialized Terms: Membrane transport; Bile formation; Cholestasis; Nuclear receptors; Bile acids; Organoids;, exosomes; Membrane targeting; Jaundice; Autoimmune hepatitis; Primary biliary cirrhosis; Sclerosing cholangitis; Hepatic drug toxicity
Extensive Research Description
Dr. Boyer's laboratory has pioneered in establishing the molecular and cellular basis for bile secretory function of the liver. In the late 1970’s, he established that the sodium pump was localized to the basolateral membrane of the hepatocytes. This work placed the hepatocyte as a more typical polarized epithelium and allowed paradigms that were developed in other polarized epithelia to be applied to the liver. For example, this finding allowed Dr. Boyer’s lab to purify canalicular membranes away from the basolateral domain and thus introduce the use of membrane vesicle preparations for studying transport activity. The development of in-vivo models for studying bile secretory functions (the hepatocytes couplet and the isolated bile duct unit) initially from rats and later from mice was also a major technical advance for the field. These models have been widely used by many investigators for the study of hepatobiliary transport function in live cell preparations without the confounding effects of blood flow inherent in intact or isolated perfused rat livers. These models also permit the localization of specific functions to either hepatocytes or cholangiocytes. His laboratory was also the first to demonstrate and annunciate the concept that hepatobiliary transporters undergo adaptive regulation in response to cholestatic liver injury both in liver and in kidney. This is an area of investigation now widely pursued by many laboratories and continues to be a current focus. This work has led to current studies of the role of nuclear receptors in the regulation of transporter expression and a search for novel therapies directed to stimulation of this adaptive response. The impact of this body of work has been recognized by the Adolf Windaus Prize presented by the Falk Foundation in 1988, the Distinguished Achievement Award from the American Gastroenterology Association in 1989, the Distinguished Achievement Award from the American Association for the Study of Liver Disease in 1998 and the Distinguished Scientific Achievement Award from the American Liver Association in 1999. The more recent discovery of a novel heteromeric organic solute transporter, Ostalph-Ost beta in the liver of the marine skate by Dr. Boyer and his colleague, Ned Ballatori has led serendipitoiusly to the finding that this is the missing link the basolateral ideal transporter)in the enterohepatic circulation of bile salts. This important discovery came from work at the Mt Desert Island biological Laboratory in Maine where Dr. Boyer and colleagues have pursued seasonal research using a comparative animal model approach with marine vertebrates for nearly 4 decades. Most recently the finding that retinoids are a potent agonist for both marine elasmobranch and human nuclear receptor FXR has led to a clinical efficacy therapeutic trialing patients with sclerosing cholangitits.
- Mechansims of bile acid induced inflammatory injury and the roel of innate immunitay in cholestasis
- The effect of retinoids and cytokine receptor blockers in an animal model of and patients with sclerosing cholangitis
- The role of MIF and CD72 as biomarkers of stress in autoimmune hepatitis
- The use of biliary organoids for drug discovery in cholestataic liver diseases
- The role of Ost-alpha/beta in regulation of lipid biosynthesis
- Evolution of bile acid transporters in vertebrates
- Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid fed mouse model of cholestasis. Kulkarni SR, Soroka CJ, Hagey LR, Boyer JL. Hepatology. 2016 Sep 17. doi: 10.1002/hep.28826. [Epub ahead of print] PMID: 27639250
- Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study. Assis DN, Abdelghany O, Cai SY, Gossard AA, Eaton JE, Keach JC, Deng Y, Setchell KD, Ciarleglio M, Lindor KD, Boyer JL. J Clin Gastroenterol. 2016 Jul 14. [Epub ahead of print] PMID: 27428727
- Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. Chai J, Cai SY, Liu X, Lian W, Chen S, Zhang L, Feng X, Cheng Y, He X, He Y, Chen L, Wang R, Wang H, Boyer JL, Chen W. J Hepatol. 2015 Dec;63(6):1440-8. doi: 10.1016/j.jhep.2015.07.016. Epub 2015 Jul 23. PMID: 26212029
- A Novel Di-Leucine Motif at the N-Terminus of Human Organic Solute Transporter Beta Is Essential for Protein Association and Membrane Localization. Xu S, Soroka CJ, Sun AQ, Backos DS, Mennone A, Suchy FJ, Boyer JL. PLoS One. 2016 Jun 28;11(6):e0158269. doi: 10.1371/journal.pone.0158269. eCollection 2016. PMID: 27351185
- Na(+) /H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury. Li M, Mennone A, Soroka CJ, Hagey LR, Ouyang X, Weinman EJ, Boyer JL. Hepatology. 2015 Oct;62(4):1227-36. doi: 10.1002/hep.27956. Epub 2015 Aug 22. PMID: 26108984
- Cai SY, Lionarons DA, Hagey L, Soroka CJ, Mennone A, Boyer JL. Adult sea lamprey tolerates biliary atresia by altering bile salt composition and renal excretion. Hepatology. 2013 Jun;57(6):2418-26
- Boyer JL. Bile formation and secretion. Compr Physiol. 2013 Jul;3(3):1035-78.
- Assis DN, Leng L, Du X, Zhang CK, Grieb G, Merk M, Garcia AB, McCrann C, Chapiro J, Meinhardt A, Mizue Y, Nikolic-Paterson DJ, Bernhagen J, Kaplan MM, Zhao H, Boyer JL, Bucala R.,The role of macrophage migration inhibitory factor (MIF) in autoimmune liver disease. Hepatology. 2013 Aug 2
- Soroka CJ, Velazquez H, Mennone A, Ballatori N, Boyer JL Osta depletion protects liver from oral bile acid load.Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G574-9. PMID:21719738
- Lam P, Xu S, Soroka CJ, Boyer JL A c-terminal tyrosine-based motif in the bile salt export pump directs clathrin-dependent endocytosis. Hepatology. 2011 Dec 12. doi: 10.1002/hep.25523. [Epub ahead of prin
- Padda, MS, Sanchez M, Akhtar AJ and Boyer JL. Drug Induced Cholestasis. Hepatology. 53(4): 1377 – 1387, 2011. PMCID: PMC3089004
- He H, Mennone A, Boyer JL, Cai SY. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology. 53(2):548-57, 2011. PMID: 21274875
- Boyer JL. It's all about bile. Hepatology. 2009 Mar;49(3):711-23
- Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009 Mar;136(3):1060-9.