Rudolf ZECHNER
Lauréat du Prix Louis-Jeantet de Médecine 2015

Rudolf Zechner est né à Graz en Autriche en 1954. Il a étudié la biochimie à l’Université de sa ville natale où il a passé son doctorat en 1980, puis il a fait son post-doctorat à l’Université Rockefeller à New York. Il est ensuite revenu à l’Université de Graz où, depuis 1998, il est professeur de biochimie à l’Institut des biosciences moléculaires.

Membre de l’Académie des sciences autrichiennes, Rudolf Zechner a déjà reçu de nombreux prix prestigieux, notamment le Prix Wittgenstein, la plus haute distinction scientifique autrichienne, ainsi qu’une subvention accordée par le Conseil européen de la recherche.

Une enzyme responsable de la dégradation des lipides

L’obésité, le diabète de type 2 et les maladies cardiovasculaires ne cessent de prendre de l’ampleur dans le monde. Ces troubles sont souvent provoqués par des dérèglements du métabolisme des lipides. Cela conduit à une accumulation de graisse et de cholestérol dans le foie et le cœur ou sur les parois des artères, et entraîne un dysfonctionnement de ces organes ou tissus.

Rudolf Zechner et ses collègues étudient les mécanismes qui régulent le métabolisme lipidique et, depuis quinze ans, ils se sont tout particulièrement intéressés à des enzymes dégradant les graisses, les lipases. Ils ont découvert une nouvelle enzyme de cette famille, la triglycéride lipase adipeuse (ATGL), ainsi qu’une protéine régulatrice de l’ATGL (CGI-58). Ces molécules biologiques sont responsables de la dégradation des lipides stockés dans pratiquement toutes les cellules de l’organisme. Cette découverte a radicalement modifié les connaissances sur la dégradation des lipides. Elle explique également les mécanismes responsables de l’apparition de maladies génétiques rares mais très lourdes, les «maladies du stockage des lipides neutres», qui sont dues à la déficience de l’enzyme ATGL ou de son co-régulateur.

Rudolf Zechner et son équipe cherchent à comprendre comment la dégradation des graisses influence le fonctionnement des cellules et la pathogénèse de différentes maladies. Ils ont ainsi mis en évidence une relation entre la dégradation des lipides dans les cellules du cœur et la fonction cardiaque. Lors d’études supplémentaires, ils ont observé de manière inattendue que la dégradation des lipides par l’ATGL jouait également un rôle important dans la cachexie, une perte de poids incontrôlée et irréversible fréquente chez les patients cancéreux. Cette découverte pourrait ouvrir la voie à de nouvelles stratégies thérapeutiques pour cette maladie.

The fate of fat – The Enzymatic Degradation of Triglycerides

“Man can learn nothing except by going from the known to the unknown” – is a quotation from the famous French physiologist Claude Bernard and archetypical for the development of the research area of Rudolf Zechner, lipid and energy metabolism. Although studied since the beginning of modern biosciences around 200 years ago, lipid and energy metabolism still remains of central interest due to its involvement in the development of extremely common diseases such as obesity, cardiovascular disease or cancer.

Animal and plant “fats” and “oils” were historically among the first biomolecules whose chemical composition was elucidated. Already during the first half of the 19th century French chemists Chevreul and Berthelot discovered that fats and oils consist of three fatty acid molecules, which are esterified with glycerol. In 1858, Bernard himself discovered an enzyme later called “lipase” that cleaves these “triglycerides” (TGs) to release fatty acids (FAs) and glycerol in a process termed “lipolysis”. The synthesis and lipolysis of TGs were recognized as essential processes in all organisms once it was understood that TGs cannot cross cell membranes. Accordingly, all fat in our nutrients must be hydrolyzed before they can be absorbed in the gut and later deposited in fat (adipose) tissue. Conversely, when fat is mobilized again from adipose tissue to supply other tissues such as heart, muscle, or liver with energy, TGs must be degraded before FAs and glycerol can be released.

Revision of the “lipolytic” dogma

Rudolf Zechner’s laboratory focuses on enzymes and mechanisms that control lipolysis in adipose tissue and other cell types. For many decades, textbook biochemistry taught that an enzyme called hormone-sensitive lipase is rate-limiting for the degradation of fat in adipose tissue. But when Zechner and colleagues eliminated this enzyme in mice, the animals unexpectedly did not accumulate fat or become obese, but instead exhibited relatively normal lipolysis. This indicated that the main enzyme for fat catabolism remained unidentified; a circumstance that led to the discovery of adipose triglyceride lipase (ATGL) by the Zechner lab. The severe fat accumulation in multiple tissues of ATGL-deficient mice soon proved the essential role of this enzyme in lipolysis. The Zechner group also demonstrated that ATGL requires a protein co-activator for full enzymatic activity called CGI-58.

Biochemical basis for an inherited human disease

The discovery of ATGL and its activation by CGI-58 finally provided a mechanistic explanation for the development of neutral lipid storage disease (NLSD) in humans, which was originally described in the 1960’s and 1970’s. Patients with this condition are characterized by the systemic accumulation of fat in multiple tissues. These symptoms clearly resembled the pathologies observed in ATGL-deficient mice. Therefore, it came as no surprise when several other groups soon reported that mutations in the genes for ATGL and CGI-58 cause various forms of NLSD. Less expected, however, was the finding that mice and humans with defective ATGL-mediated lipolysis not only accumulate fat in tissues and cells but also develop severe dysfunctions in multiple organs including the heart (ATGL-deficiency) or the skin (CGI-58 deficiency).

Lipolysis, lipid signaling, energy metabolism

This complex disease profile suggested that defects in lipolysis not only regulate fat storage but also affects other metabolic pathways and energy metabolism (outlined in Fig. 1), which may be related to the pathogenesis of disease. In this context, Zechner’s laboratory was able to show that ATGL deficiency in cardiac muscle has a major impact on heart function via nuclear receptor signaling and mitochondrial function. Other quite recent results from his group demonstrated that lipolysis is involved in the pathogenesis of cancer-associated cachexia (CAC). Cachexia is a devastating condition of uncontrolled loss of adipose and muscle mass commonly observed in patients with cancer and other chronic diseases. CAC is associated with a very poor prognosis for survival. Zechner’s group showed that in the absence of ATGL, the development of CAC can be delayed in certain mouse models of cancer.

The future

Exciting recent work of the Zechner lab uncovered a metabolic « crosstalk » between lipolysis and lipid synthesis in adipose tissue, but it is currently unknown how these processes communicate with each other on molecular terms. The Louis-Jeantet Prize will help to clarify these mechanisms and investigate how this form of crosstalk contributes to cellular and organismal (dys)function. Additionally, the grant will finance the search for currently unknown enzymes involved in lipid catabolism. The powerful combination of tremendous resources of genome data together with innovative screening methods will facilitate the discovery of new enzymes that contribute to the catabolic turnover of lipids. The medical relevance of this work is evident considering the growing prevalence of human metabolic disorders.
Fig. 1. Lipolysis and its connection to other metabolic and signaling pathways.

Lipolysis of TGs occurs on lipid droplets (yellow) via the enzymatic activities of ATGL, HSL, and MGL. Lipolysis generates FAs and glycerol. FAs and the lipolytic intermediates DGs and MGs are important signaling lipids or precursors for signaling lipids. Additionally, they are major energy substrates and precursors for the synthesis of membrane lipids. Alterations in lipolysis may alter these pathways and contribute to the development of metabolic diseases listed in red.

Abbreviations: ACSL, acyl-CoA synthetase; ATGL, adipose triglyceride lipase; CGI58, comparative gene identification-58; CoA, Coenzyme A; DG, diglyceride; FA, fatty acid; FATP, FA transport protein; HSL, hormone-sensitive lipase; MG, monoglyceride; MGL, MG lipase; TG, triglyceride;

Professeur Rudolf Zechner

Karl Franzens University of Graz
Institute of Molecular Biosciences
Heinrichstrasse 31
8010 Graz
Autriche

Telephone: +43 316 380 1900


http://dk.uni-graz.at