Research & Publications
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 bile derived organoids and cell lines for drug discovery. Trainees utilize a variety of fundamental techniques ranging from general cell biologic and molecular biologic procedures, as well as organoid development from human liver and bile, to advanced morphologic approaches including fluorescent and confocal scanning microscopy. This research has been supported by NIH grants, core facilities provided by an NIH Liver Center and donations.
Specialized Terms: Membrane transport; Bile formation; Cholestasis; Nuclear receptors; Bile acids; Organoids;, exosomes; Membrane targeting; Jaundice; Autoimmune hepatitis; Primary Biliary Cholangitis; 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 permited 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 subsequently widely pursued by many laboratories . This work has led to 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 discovery of a novel heteromeric organic solute transporter, Ost alpha-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. Currently his lab is studying the mechanisms by which bile acids activate an inflammatory casade in hepatocytes and cholangiocytes and have pioneered in the development of human bile derived organoids to study the mechansimf of the disease, Primary Sclerosing Cholangitis. 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. In 2020, he received the European Association of the Study of the Liver's prestigious International Recognition Award.
- Mechansims of bile acid induced inflammatory injury and the role of innate immunity in cholestasis
- The use of biliary organoids for drug discovery in cholestatic liver diseases.
Bile; Cholestasis; Digestive System Diseases; Jaundice; Liver; Organoids; Cholangitis, Sclerosing