James Lorenzen Boyer MD
Ensign Professor of Medicine (Digestive Diseases); Emeritus Director, Yale Liver Center
Membrane transport; Bile formation; Cholestasis; Nuclear receptors; Bile acids; Membrane targeting; Jaundice; Autoimmune hepatitis; Primary biliary cirrhosis; Sclerosing cholangitis; Hepatic drug toxicity
- The effect of retinoids in an animal model of and patients with sclerosing cholangitis
- The role of MIF and CD72 as biomarkers of stress in autoimmune hepatitis
- Understanding how mutations in the Bile Salt Export Pump (BSEP) lead to cholestasis in children with progressive familial intrahepatic cholestasis
- The role of NHERF-2 (EBP50) in the regulation and expression of Multidrug resistance protein-2 (Mrp2)
- The lamprey as a novel model of biliary atresia
- Evolution of bile acid transporters in vertebrates
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 adaptive responses of hepatobiliary transporters to cholestasis and involve both studies of nuclear receptor transcriptional and post-transcriptional regulators. 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.
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.