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In memoriam: the maestro of bile acids: Alan F. Hofmann (1931–2021)

2021; Elsevier BV; Volume: 62; Linguagem: Inglês

10.1016/j.jlr.2021.100137

1539-7262

Paul A. Dawson, Lee R. Hagey, Aldo Roda,

Pediatric Hepatobiliary Diseases and Treatments

Bile acid researchers throughout the world were saddened to learn of the death of Alan F. Hofmann, Professor Emeritus of Medicine at the University of California, San Diego (UCSD), on September 7, 2021. Alan was an internationally renowned basic scientist and clinical investigator, whose more than 60 years of research shaped and transformed our understanding of the chemistry, biology, and physiology of bile acids in health and disease. His long and remarkable career was marked by seminal scientific discoveries and by his service as an ambassador for the field of "cholanology" (the science of bile acids) to attract, educate, and inspire new generations of physicians and scientists. Alan Hofmann was born on May 17, 1931 to Joseph and Nellie Hofmann and grew up in Baltimore, MD. He graduated from Baltimore City College for High School and was awarded a full scholarship to Johns Hopkins University. Besides his academic subjects, Alan Hofmann also played bass violin in the orchestra, sousaphone in the band, and sang glee club. He graduated with academic honors in 3 years and remained at Johns Hopkins for Medical School, having been awarded a full academic scholarship. After completing his internship at Columbia-Presbyterian, and a stint as a clinical associate at the National Institutes of Health, Alan Hofmann's career was at a crossroads. At the National Institutes of Health, he became interested in the problem of fat digestion and believed that the most knowledgeable person on the subject at that time (∼1959) was the lipid biochemist Bengt Borgström in Sweden. While waiting to hear about his fellowship application to study with Dr Borgström, Alan Hofmann left the National Institutes of Health to join the National Symphony as an accompanying physician on its Pan American tour. It was in Peru that Alan Hofmann learned his fellowship would be funded and he was soon off to the University of Lund. Over the next 3 years, Drs Hofmann and Borgström conducted their groundbreaking work to elucidate the physicochemical properties of bile acids in solution and their relationship to fat absorption, as well as showing that the ileum is the major site of conjugated bile acid absorption in humans. For his thesis describing this work, Alan Hofmann received an MD (equivalent of a PhD) from the University of Lund in 1965, and it was with a twinkle in his eye that Alan Hofmann traveled back to Lund in 2015, where on May 29, he was celebrated as a "Jubeldoctor" (Jubilee doctor, honorary doctorate awarded 50 years after the original doctorate). For these discoveries regarding lipid digestion and absorption, the American Gastroenterological Association (AGA) recognized Alan Hofmann in 1970 with a Distinguished Achievement Award, and Drs Hofmann and Borgström were awarded the William Beaumont Prize in 1979. After returning from Sweden, Alan Hofmann joined Rockefeller University in New York, where he worked with Scott Grundy to study the impact of bile acids on cholesterol metabolism in humans and fostered a productive outside collaboration with Erwin Mosbach to understand the principles underlying calcium-bile acid interactions in bile. In 1966, Alan Hofmann moved to the Mayo Clinic in Rochester, where he served as the codirector of clinical and basic gastrointestinal research until 1977. Alan Hofmann thrived at the Mayo. It was there that Alan Hofmann, together with a remarkable group of collaborators and talented fellows that included Sydney Phillips, Hanns Fromm, Leslie Schoenfield, Rudy Dazinger, Rainer Poley, Johnson Thistle, Nicholas LaRusso, and Tim Northfield, made major advancements in our understanding of bile acid malabsorption, the kinetics of daily bile secretion and enterohepatic cycling in humans, and oral bile acid (chenodeoxycholic acid) therapy for dissolution of cholesterol gallstones. Since 1977, Alan Hofmann has been a Professor in the Department of Medicine at the UCSD. There, Alan Hofmann and collaborators worked to define the relationship between bile acid structure and micelle formation and to further our understanding of the physiology and pharmacokinetic principles underlying the enterohepatic circulation of bile acids. Particularly fruitful was his work with Karol Mysels at UCSD, a renown physical chemist and expert on micelles and surface tension, and Aldo Roda, a chemist and visiting scholar from the University of Bologna. Together, they advanced our understanding of the relationship between bile acid structure and self-aggregation for micelle formation in solution. This work (1Roda A. Hofmann A.F. Mysels K. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar) remains highly cited and opened new perspectives on the design of semisynthetic bile acid analogs as drugs. Alan Hofmann was always excited about advances in bioanalytical methods for measuring bile acids and helped develop the first radioimmunoassay for primary bile acids and worked with Gerard van Berge Henegouwen on the use of gas-liquid chromatography while at the Mayo Clinic. This work continued at UCSD with the development of a simple and sensitive bioluminescent assay for serum primary bile acids (with Aldo Roda), a precursor to biosensors and point-of-care testing, and application of state-of-the-art mass spectrometry-based methods to the study of bile acids and bile acid metabolites. Together with his close colleague, Lee Hagey (http://bile.ucsd.edu/), Alan Hofmann launched an ambitious program to understand the remarkable diversity of chemical structures in the three great bile salt classes, C27 bile alcohols, C27 bile acids, and C24 bile acids, building upon the work of the late Geoffrey Haslewood, Professor of Biochemistry at Guy's Hospital Medical School in London. Much of this work appeared in the Journal of Lipid Research, including analysis of the biliary bile salt analysis of 677 vertebrate species with Matthew Krasowski in 2010 (2Hofmann A.F. Hagey L.R. Krasowski M. Bile salts of vertebrates: structural variation and possible evolutionary significance.J. Lipid Res. 2010; 51: 226-246Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). In 1994, Alan Hofmann was awarded the Friedenwald Medal from the AGA for his many discoveries over the previous 35 years. When asked how he may wind down his career, Alan Hofmann was quoted as saying: "I want to know why we have these molecules. We started off believing that bile acids helped us absorb lipids. We clarified that. Next, we clarified their role in the liver—how they induce bile flow and lipid secretion. But I am not sure that is the answer." Over the next 27 years, Alan saw his work and influence on the field foster a bile acid renaissance, with the emergence of new answers to his question and exciting advances in our understanding of bile acids as signaling molecules and regulators of metabolism and the microbiome. During this period and in keeping with his goal of "trying to understand the chemistry and biology of bile acids with the hope of helping patients," Alan Hofmann and his work directly and indirectly catalyzed the development of new bile acid-related therapeutics. This includes approved therapies such as the second-generation bile acid sequestrant colesevelam, the semisynthetic farnesoid X-receptor agonist obeticholic acid, and ileal bile acid transporter inhibitors odevixibat and maralixibat, and bile acid-based therapies in development such as the bile salt hydrolase-resistant bile acid analog cholylsarcosine as bile acid replacement therapy for short bowel syndrome, 11C-cholylsarcosine for use in positron emission tomography imaging, and the side chain shortened bile acid analog, norursodeoxycholic acid (norucholic acid), for primary sclerosing cholangitis. The story behind obeticholic acid is illustrative of Alan Hofmann's influence. At a party in the early 1980s at UCSD, Alan Hofmann and Aldo Roda met Roberto Pellicciari, a visiting professor in Medicinal Chemist from Perugia. After returning to Italy, Drs Roda and Pellicciari initiated a collaboration to design, synthesize, and study the physicochemical properties of new bile acid analogs. This culminated in the discovery of obeticholic acid (6α-ethyl-chenodeoxycholic acid) by Roberto Pellicciari, who was motivated by Alan Hofmann's encouragement and his prediction of the existence of bile acid receptors. Alan Hofmann will be remembered for his enthusiasm, creativity, and sense of humor. Alan Hofmann generously shared his encyclopedic knowledge of bile acids and was an early mainstay of National and International Bile Acid Meetings. Alan Hofmann co-organized (with Luigi Barbara and Enrico Roda from the University of Bologna) the Biennial Congress on Bile Acid Research at the Italian mountain village of Cortina d'Amprezzo in 1975 and subsequent years, and organized in 1983 the last Kroc Foundation Conference on the Physical Chemistry of Bile in Health and Disease. The Kroc Foundations Conference convened a remarkable group of individuals from the physical and biomedical sciences, and a picture and list of the participants is shown. In 1972, Alan Hofmann together with Gustav Paumgartner launched with Biennial International Bile Acid Meetings, which continue to be supported by the Falk Foundation, and remain an outstanding venue to present advances in bile acid biology, chemistry, and therapeutics. During his career, Alan Hofmann published over 500 original articles and invited contributions as well as 51 reviews. The Journal of Lipid Research remained one of Alan Hofmann's favorite journal to publish his basic research on bile acids, including an authoritative history of key discoveries in bile acid chemistry and biology over the past 8 decades (3Hofmann A.F. Hagey L. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades.J. Lipid Res. 2014; 55: 1553-1595Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Alan Hofmann also made two short films, edited nine books, coauthored one book, cofounded the Undergraduate Teaching Project of the AGA and published four sets of teaching materials in gastrointestinal physiology and pathophysiology. In addition to the awards mentioned previously, Alan Hofmann has been the recipient of many other honors and honorary degrees. These include an honorary degree in medicine from the Alma Mater Studiorum University of Bologna Italy (1988), the Davenport Medal from the American Physiological Society (1996), the Thannhauser Medal from the Germany Society for Gastroenterology, Digestive and Metabolic Diseases (1996), a Distinguished Achievement Award from the American Association for the Study of Liver Diseases (1997), and Herbert Falk Medal (2010) from the Falk Foundation. Alan Hofmann's legacy is embodied in his lasting impact on the bile acid field, the patients that his findings have helped or will help in the future, and the shared memories of his family and his many friends and admirers from around the world. Alan is survived by Heli Hofmann, his wife of 43 years, two daughters Anthea and Cecelia from his first marriage, two stepdaughters Caroline and Isabel, and five grandchildren. His passing leaves an immeasurable void, and he will be greatly missed.