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Rolf Gebhardt University of Leipzig Medical Fakulty Institute of Biochemistry Garlic & Health: WP 5.2 Effect of Garlic on Cholesterol Biosynthesis.

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Presentation on theme: "Rolf Gebhardt University of Leipzig Medical Fakulty Institute of Biochemistry Garlic & Health: WP 5.2 Effect of Garlic on Cholesterol Biosynthesis."— Presentation transcript:

1 Rolf Gebhardt University of Leipzig Medical Fakulty Institute of Biochemistry Garlic & Health: WP 5.2 Effect of Garlic on Cholesterol Biosynthesis

2 Topics: 1.Differential Effects of Garlic Extracts on Cholesterol-Biosynthesis -Sulfur fertilization -Environmental influences 2.Influence of Garlic Organosulfur Compounds: -Mechanistic studies 3. Consequences and Conclusions

3 Methods: 1.Use of human HepG2 cells or primary cultures of rat hepatocytes 2.Determination of HMGCoA reductase activity 3.Incorporation of radiolabeled acetate into steroids, mainly cholesterol (> 90%) 4.Studies on HMGCoA reductase regulation (phosphorylation of model peptides)

4 Cholesterol Biosynthesis is highly regulated at various steps among others HMGCoA reductase is a key enzyme Many important biomolecules are derived from intermediates of cholesterol biosynthesis -->the biosynthetic pathway should never be completely inhibited

5 Garlic Powder: reinvestigation Garlic Powder: expected influence Inhibition of cholesterol biosynthesis 0.010.11 Concentration (mg/ml) 0 20 40 60 80 100 120 140 160 Cholesterol Biosynthesis (%) Hepatoc. HepG2 fresh Garlic 1

6 Garlic Powder: reinvestigation Unexpected Result !! Garlic Powder (Low Quality Garlic): Stimulation of cholesterol biosynthesis !

7 Field Study on Garlic Quality: 1.Controlled planting of four defined garlic varieties in two different european countries 2.Controlled variation of soil fertilisation 3.Standardized harvesting, drying and powder preparation 4.HPLC characterisation of organosulfur content by standardized techniques in two laboratories

8 Influence of fertilization on garlic properties Proper fertilization may change the response of hepatic cells with respect to cholesterol biosynthesis: Stimulation may turn into inhibitionInhibiting properties may be reinforced

9 Influence of fertilization on garlic properties Influence of fertilization: comparison of French harvest 2000 - 2001 Qalitatively similar results in both years

10 Influence of fertilization on garlic properties Influence of high sulfur fertilization: French harvest 2001

11 Influence of fertilization on garlic properties Influence of high sulfur fertilization: French harvest 2001 Too much sulfur may reduce potency again

12 Environmental influence on garlic properties Comparison of French and Spanish harvest 2001 Only stimulation is found with spanish garlicToo much sulfur may reduce potency again

13 Topics: 1.Differential Effects of Garlic Extracts on Cholesterol-Biosynthesis -Environmental influences 2.Influence of Garlic Organosulfur Compounds: -Mechanistic studies 3.Consequences and Conclusions

14 Comparison of different garlic-derived organosulfur compounds for inhibition of cholesterol biosynthesis

15 Inhibition of HMGCoA reductase and cholesterol biosynthesis Test Compound EC 50 values HMGCoACholesterol reductasebiosynthesis Allicin> 300 17 Diallyl disulfide> 250 65 Allyl mercaptan> 1500 450 S-allyl cysteine n.d. > 1500 Diallyl sulfide> 1000 735 Dipropyl disulfide> 1500 > 1000

16 Regulation of HMGCoA Reductase Mechanism Regulators Transcription: SREBP-1,-2Insulin, Cholesterol, LXROxysterols Protein degradationMevalonate, Calpain-Inh. Protein-Phosphorylation AMP-dependent kinaseAMP, low energy charge Protein kinase CHormones Calmodulin-dep. kinaseCalcium, hormones

17 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

18 Effect of fructose on hepatocellular ATP level Fructose

19 Effect of fructose and DADS on AMP-dep. kinase fructose fructose + DADS

20 Effect of fructose and DADS on AMP levels, AMP-dep. kinase and cholesterol biosynthesis Condition AMP AMPK Cholesterol biosynthesis (nmoles/mg)(%) (%) Control0.34100 100 Fructose5.78523 54 Diallyl disulfide0.50157 92 Fructose + DADS4.85686 25 Fruct. + DADS + araA4.56194 93

21 Effect of hypoxia, KCl and DADS on AMP levels, AMP-dep. kinase and cholesterol biosynthesis Condition AMP AMPK Cholesterol biosynthesis (nmoles/mg)(%) (%) Control0.41100 100 low oxygen4.75408 72 low oxygen + DADS4.59566 59 KCl2.58346 79 KCl + DADS2.73424 63 KCl + DADS + araA2.46170 89

22 Correlation between AMPK activity and inhibition of cholesterol biosynthesis Correlation coefficient: r = - 0.96 for all conditions: - absence of DADS (closed symbols) - presence of DADS (open symbols)

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

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

25 Basic properties of the indirect influence on HMGCoA reductase: 1. Regulation in harmony with cellular requirements: i.e. in cases of dysregulation 3. No complete shut-off of cholesterol biosynthesis (no loss of important intermediates) 4. Restricted to organs with high AMPK activity: (liver, heart, muscle - no hormone secreting glands) 2. Increased sensitivity only when needed

26 Summary: 1.Sulfur fertilisation seems to influence the potential of garlic extracts to inhibit or stimulate hepatic cholesterol-biosynthesis 3.Garlic organosulfur compounds may sensitively inhibit cholesterol biosynthesis under stress-like conditions 2.The nature of stimulatory compounds is still unknown

27 Flavonoids in Garlic: University of Leipzig Literature Results Starke & Hermann, 1976only trace amounts of quercetin and Michahelles, 1974kaempferol in peeled garlic Kaneta et al., 1980 Leighton et al., 1992 Carotenuto et al., 1996Kaempferol-glycosides in Allium ursinum (no quantitative data) Miean & Mohamed, 2001detailed HPLC analysis, but poorly described plant material Myricetin693 mg/kg dry weight Quercetin 47 Luteolin not detectable Apigenin217

28 Structure of Favonoids used University of Leipzig All tested flavonoids belong to the flavonol group They differ only in the amount and/or position of one or two hydroxyl groups In the case of Luteolin and Kaempferol, several glycosides were also tested

29 University of Leipzig Comparison of the effects of Kaempferol, Luteolin and their glycosides in rat hepatocytes Kaempferol: sensitive stimulation of cholesterol biosynthesis high cytotoxicity (responsible for decline) Luteolin: inhibition of cholesterol biosynthesis (no significant stimulation) low cytotoxicity

30 University of Leipzig Comparison of the effects of Myricetin, Kaempferol and Luteolin in HepG2 cells Myricetin: stimulation of cholesterol biosynthesis Kaempferol: no significant effect Luteolin: inhibition of cholesterol biosynthesis

31 Garlic & Health: WP5 Cholesterol and cytokines University of Leipzig Aim:Interaction of garlic constitutents with vessel wall Inhibition of Matrix Metalloproteinase-2 Production by DADS, AM and SAC in HCA- endothelial cells

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