Professor Kalervo Hiltunen:
|Professor Kalervo Hiltunen
University of Oulu
Dr. Kalervo Hiltunen is Professor of Biochemistry and the work described herein is a continuation of long-term research on cellular lipid biochemistry carried out by our group at Biocenter Oulu and Department of Biochemistry. Lipid metabolism is a compartmentalized process that differs between organs, cell types and also within a cell in different subcellular organelles. Compartmentalized processes require co-ordinated interaction between the cell organelles governed by targeted transport of molecules, signal transduction across biomembranes and special mechanisms for transport of lipids. Hiltunen’s group will contribute to the programme by providing genetically modified mouse models for studies on the effect of nutrition derivated modified lipids and mice phenotype analyses. Other research of this partner brings to the programme is the structural biology of lipid metabolizing enzymes.
We have recently generated an Amacr -/- mouse strain. As the mouse strain is not able to carry our α -methylacyl-CoA racemase (Amacr)-dependent chain shortening of the side chain of cholesterol during the bile acid synthesis, the knock-out strain was assumed to present “life without bile acids”. Surprisingly, the Amacr -/- mice were clinically symptonless until the diet was fortified with phytol, a branched chain fatty acid precursor from plant chlorophyll. The wild type mice tolerated well this diet whereas Amacr -/- mice died. Therefore, we concluded that the key function of Amacr is the elimination and detoxification of methyl-branched fatty acids. Taking into account the crucial role of bile acids in cholesterol metabolism and digestion, the Amacr-/- mice had mild disturbance in phenotype when kept on standard laboratory diet. Hence, what is the role of racemase in lipid metabolism? What are the roles of bile acids, oxysterols and branched chain fatty acid metabolites as regulators of intermediary metabolism? Detailed phenotype analysis of Amacr-/- mice is ongoing, including analysis of cholesterol and bile acid metabolite profiles and lipid absorption. A DNA microarray approach has been started for global monitoring of gene expression patterns.
Concerning metabolism of modifed (polyunsaturated) fatty acids, a mouse strain defective in 120kDa mitochondrial 2,4-dienoyl-CoA reductase (DECR) has been generated. In Decr-/- mice the mitochondrial β -oxidation of fatty acids with double bonds at even or odd-numbered positions is expected to be inhibited. The Decr-/- mice present a highly unexpected phenotype by linking together gluconeogensis and degradation of polyunsaturated fatty acids. This link cannot be easely explained in terms of current knowledge on metabolic regulation.
In recent years, mitochondrial research has been attracting significant attention, largely due to the recognition of inherited diseases of mitochondrial origin and the discovery that these organelles are intimately tied to apoptotic events in higher eukaryotes. Similarly to other lipid metabolizing processes, FAS can take place in at least two subcellular compartments in eukaryotic cells: in the cytoplasm (FAS type 1, the individual reactions are carried out by a multifunctional fatty acid synthetase complex), and in mitochondria (FAS type 2; also in the chloroplasts of plant cells) where the enzymes are separate entities. This raises the question of why eukaryotes have maintained the bacterial type FAS in their mitochondria in addition to the “classic” cytoplasmic FAS. Surprisingly, the ability of mitochondria to synthesize fatty acids is linked to mitochondrial respiratory function as well as to the size of the mitochondrial population in the cell.
Asubstantial portion of our research effort is addressed to the chemical and mechanistical aspects of lipid metabolism and structure-function relationships of fatty acyl-thioester metabolizing enzymes: How have the enzymes evolved to be able to degrade a large variety of modified compounds, for example with molecules a different degree of unsaturation as well as having been modified further by the presence of extra methyl or hydroxy groups? Multifunctional enzymes (MFEs) appear to be important player in these processes.
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