Rolf Gebhardt University of Leipzig Medical Faculty Institute of Biochemistry Garlic & Health: WP 5.2 Effect of Garlic Compounds on Cellular Signalling.

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Presentation transcript:

Rolf Gebhardt University of Leipzig Medical Faculty Institute of Biochemistry Garlic & Health: WP 5.2 Effect of Garlic Compounds on Cellular Signalling

Topics: 1.Interference of Garlic Compounds with Cholesterol-Biosynthesis -Role of AMPK 2.Structure and Function of AMPK -Interaction with other signalling pathways 3.New Results on the Effects of DADS and Conclusions

Schematic view of the probable mode of action of several garlic-derived organosulfur compounds

Effect of fructose and DADS on AMP levels, AMP-dep. kinase and cholesterol biosynthesis Condition AMP AMPK Cholesterol biosynthesis (nmoles/mg)(%) (%) Control Fructose Diallyl disulfide Fructose + DADS Fruct. + DADS + araA

Effect of hypoxia, KCl and DADS on AMP levels, AMP-dep. kinase and cholesterol biosynthesis Condition AMP AMPK Cholesterol biosynthesis (nmoles/mg)(%) (%) Control low oxygen low oxygen + DADS KCl KCl + DADS KCl + DADS + araA

Correlation between AMPK activity and inhibition of cholesterol biosynthesis Correlation coefficient: r = for all conditions: - absence of DADS (closed symbols) - presence of DADS (open symbols)

Influence of fructose, i.e. high AMP on the sensitivity of hepatocytes towards DADS Lowering of the cellular energy charge - increases the sensitivity towards DADS 5- to 10-fold

Topics: 1.Interference of Garlic Compounds with Cholesterol-Biosynthesis -Role of AMPK 2.Structure and Function of AMPK -Interaction with other signalling pathways 3.New Results on the Effects of DADS and Conclusions

AMPK AMPKK PP2A AMP Nutrients Stress Exercise Glucose transport ß-Oxidation of fatty acids Fatty acid synthesis Cholesterol synthesis Apoptosis Transcription Creatine kinase Signalling RAF-1 ? (after Kemp et al. TIBS 2000;24:22-25) Central Role of AMP-dependent kinase (AMPK) as a mediator of stress signals, e.g. low energy charge Energy consuming pathways e.g. fatty acid and cholesterol synthesis are shut down

Subunit structures of AMPK P P Catalytic domain Autoregulatory domain Subunit-targeting domain AMPK-a1 AMPK-a2 PPP P AMPK-b1 AMPK-b2 CßS AMPK-g1 AMPK-g2 AMPK-g3 (according to Kemp et al., TIBS 1999;24:22-25)

Basic properties of AMPK: 2. Regulated by a) the AMP-level (AMP/ATP ratio) b) various phosphorylation events 3. Present not only in the cytosol but also in the nucleus (--> may participate in controlling of transcription factors) 4. Participates in a variety of signalling events: e.g. leptin signalling biogenesis of mitochondria AMPK knockouts are diabetic! 1. Acts as a „fuel gauge“ in every cell and tissue (organs with high AMPK activity: liver, heart, muscle - lowest in hormone secreting glands)

Mediation by AMPK of chronic energy depletion-induced mitochondrial biogenesis GPA ATP / AMP + CaMK IV PGC-1a mitochondrial biogenesis + AMPK

Influence of ß-guanidinopropionic acid (GPA) and DADS on mitochondrial MTT reduction in muscle cells Lowering of the cellular energy charge - increases mitochondrial MTT-reducing capacity

Influence of ß-guanidinopropionic acid (GPA) and DADS on mitochondrial cytochrome c content in muscle cells Lowering of the cellular energy charge - increases the sensitivity towards DADS GPA and DADS - synergistically increase mitochondrial cytochrome c content

Effects of antidiabetic drugs Rosiglitazone Metformin Insulin sensitivity blood glucose level - peripheral glucose uptake -fatty acid oxidation -fatty acid esterification - hepatic glucose production

Role of AMPK as a mediator of antidiabetic drugs Rosiglitazone or DNP ATP / AMP + + AMPK antidiabetic effects Metformin or hyperosmolar stress + + ? Phosphorylation at Threonine 172

Influence of insulin and DADS on glucose production in normal rat hepatocytes Insulin: - lowers glucose production DADS: - has no influence in normal rats

Influence of insulin and DADS on glucose production in obese Zucker (fa-/fa-) rat hepatocytes Insulin: - slightly lowers glucose production DADS: - reinforces the insulin effect in obese rat hepatocytes

Conclusion: 1. DADS influences glucose production in diabetic rats, but not in normal rats 2. DADS acts only in synergy with insulin Does DADS increase sensitivity of diabetic hepatocytes for insulin? Question:

Summary and Questions: 1.DADS seems to activate AMPK under conditions associated with high levels of AMP (hypoxia, high fructose, various drugs) 3.Do garlic organosulfur compounds act on AMPK also by influencing phosphorylation of this enzyme? 2.Which garlic organosulfur compounds besides DADS have a similar effect on AMPK activity?