Kjell Wikvall

Short presentation

Kjell Wikvall, professor of biochemistry (2000) and professor emeritus at the Department of Pharmaceutical Biosciences since 2016. His research interests concern the biochemistry and molecular biology of steroids with a focus on enzymes and regulatory mechanisms in physiologically important processes such as the bioactivation of vitamin D, the biosynthesis of bile acids and steroidogenesis. He has also devoted great interest to teaching and has received several educational awards.

Biography

Kjell Wikvall was born 1949 in Karlskrona, Sweden. He started medical school at Karolinska Institute, Stockholm in 1968.

He defended his doctoral thesis (PhD) in Medical Chemistry at Karolinska Institute in 1977. Thesis title: Studies on reconstituted hydroxylase activities in biosynthesis and metabolism of bile acids, supervisor: Prof. Henry Danielsson.

He graduated from medical school (MD) in 1978 and became associate professor (docent) in Medical and Physiological Biochemistry at Uppsala University in 1981 and senior university lecturer (universitetslektor) in Pharmaceutical Biochemistry 1983.

Kjell Wikvall was appointed professor of Biochemistry in 2000 at the Department of Pharmaceutical Biosciences, Uppsala University. Since 2016, he is professor emeritus and continues to work at the department.

Kjell Wikvall has been director of studies in Pharmaceutical Biochemistry, deputy head of Department of Pharmaceutical Biosciences and chair of the Faculty of Pharmacy's Scholarship Committee for many years. He has taken a great interest in teaching and received several educational awards, including the Uppsala University Distinguished Teaching Award.

As professor emeritus, he is now course director for a research-oriented elective and independent course, Molecular Mechanisms of Enzymatic Activation (autumn semesters).

Kjell Wikvall has published over 100 scientific articles in international journals. He has been the main supervisor for 17 doctoral students and assistant supervisor for 4 doctoral students, who have defended their doctoral degrees for Doctor of Philosophy (Faculty of Pharmacy). His research has been supported for about 20 years by the Swedish Medical Research Council and the Swedish Research Council - Medicine.

Research

Kjell Wikvall's research interests relate to steroid biochemistry and cell biology focusing on enzymes, genes and regulatory mechanisms in the formation and metabolism of bile acids, oxysterols and the metabolic activation of vitamin D to a hormone. The research aim to understand the related cellular functions in health and disease. When Wikvall began his research work during the 1970s, the enzymes and genes in these processes were unknown.

Wikvall and co-workers isolated and purified during the 1980s and 1990s several enzymes necessary for the formation of bile acids, oxysterols and the bioactivation of vitamin D. An overall strategy in Wikvall's early research was to obtain important knowledge of the catalytic properties of the purified enzymes and to report partial amino acid sequences for the isolated proteins, aiming to cDNA cloning of each enzyme. The early biochemical efforts led to molecular biologically oriented projects regarding regulatory mechanisms for the respective genes in cells from different tissues. Below is an overview of Kjell Wikvall's research.

Enzymes in the biosynthesis of bile acids

Wikvall showed during his doctoral work at the Karolinska Institute that important hydroxylating enzymes in the formation of bile acids from cholesterol were cytochrome P450 dependent. After moving to the Pharmaceutical Faculty in Uppsala in 1977, he succeeded to purify two enzymes in the biosynthesis of bile acids from rabbit liver to apparent homogeneity (the sterol 27-hydroxylase and the 3β-hydroxy-D5-C27-steroid oxidoreductase). The enzymes were characterized for catalytic properties, substrate specificity and partial amino acid sequence. These pioneering biochemical efforts led directly to the first cDNA cloning of an enzyme in the bile acid biosynthesis (the sterol 27-hydroxylase CYP27A1), and is considered to be “the start of the molecular era of bile acid metabolism in which many of the early mysteries concerning the pathway and its regulation were solved. Wikvall´s purification successes inspired the subsequent isolation of the enzyme catalyzing the initiating and rate-limiting step in bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). By 1989/1990, advances in membrane protein purification and scale-up allowed three laboratories to exploit earlier observations of Wikvall et al. to isolate the protein in near homogeneous form and to clone the encoding cDNA.” (Russell DW, J Lipid Res. 2009, vol 50, S 120-125.   https://doi.org/10.1194/jlr.R800026-JLR200). Wikvall has also been interested in the formation of species-specific bile acids, especially in pigs. The group reported cDNA cloning of two enzymes in the pig's bile acid biosynthesis (CYP4A21 and CYP8B1). Comparative aspects between the enzymes of the human and pig bile acid biosynthesis were investigated and discussed.

Enzymes in the bioactivation and metabolism of vitamin D

Wikvall introduced in the 1980s research in Uppsala on enzymes in the bioactivation of vitamin D to the potent hormone calcitriol. First, a gender-specific vitamin D 25-hydroxylase was purified from male rats (CYP2C11) and then 25-hydroxylating enzymes also from rabbit and pig. After molecular cDNA cloning, the enzyme from rabbit could be identified as CYP27A1 and the enzyme from pig as CYP2D25, a previously unknown cytochrome P450 enzyme. Wikvall was early interested in the enzyme CYP27A1, which was shown to be a multifunctional enzyme, essential for the formation of bile acids but which could also perform the 25-hydroxylation of vitamin D3. Wikvall's findings were confirmed by research groups in Japan and the United States. Together with his colleague Maria Norlin and co-workers, Wikvall continued with projects on the regulation of the gene expression for various enzymes in the vitamin D metabolism. Interest has also been devoted to drug-mediated gene regulation of the vitamin D metabolism in cells in order to understand molecular mechanisms behind unfavorable effects on vitamin D status and bone health during treatment with certain drugs.

Enzymes in the biosynthesis and metabolism of oxysterols

During Wikvall's work in the 1980s with purification of enzymes in the bile acid biosynthesis, various enzyme fractions were isolated that were active in 7a, 25- and 27-oxygenation of sterols. At that time, oxysterols were known mainly as intermediaries in bile acid biosynthesis but have now been found to have hormone-like activities on their own. CYP7A1 and CYP27A1 could be identified as responsible for the formation of 7a- and 27-hydroxycolesterol, respectively. Wikvall and co-workers reported that CYP27A1 can produce also 24- and 25-hydroxycholesterol and that the gene is under hormonal regulation. During the latter part of the 1990s, Wikvall and Maria Norlin began studying enzymes that metabolize and inactivate oxysterols. A liver enzyme was purified and shown to carry out 7a-hydroxylation of both oxysterols and some neurosteroids. This enzyme was identified as CYP7B1. In other experiments with a recombinant expressed enzyme, it emerged that CYP7A1 can perform 7a-hydroxylation of two important oxysterols. CYP7A1 was previously known as specific for cholesterol in bile acid biosynthesis.

Regulatory effects by calcitriol, oxysterols and bile acids on the function of different cells

Wikvall, Norlin and their coworkers have recently studied the effects of calcitriol on the function of different cell types. Calcitriol was shown to affect hormone production in cells from adrenal gland and a new mechanism for vitamin D-mediated transcriptional regulation of a steroidogenic enzyme was reported. The group has reported results on potential calcitriol-mediated regulation of steroidogenesis even in cells from brain. An example is the discovery that synthetic vitamin D analogs inhibit proliferation and migration of a human cell line from the severe brain cancer disease glioblastoma multiforme. The results could suggest a possible role for this type of compounds in combination treatment of brain cancer.

Kjell Wikvall was assigned the title Professor Emeritus in 2016 and is affiliated with the Steroid Biochemistry Group (Maria Norlin) within the Cell Biology Unit at the Department of Pharmaceutical Biosciences, Uppsala University. His current research interests are continued studies on the effects and mechanisms of bile acids, oxysterols, calcitriol and other vitamin D metabolites in the regulation of cell function in the brain.