Cholesterol, malaria, phytosterols

The plasmodium parasite needs cholesterol for survival and multiplication. The replicative capacity of plasmodium liver forms is remarkable, achieving the fastest growth rates known.
Plasmodium starts its lifecycle in the liver because it is the place where it finds a large supply of this molecule.
Cholesterol either originates from the diet or is synthesized, mostly in the liver. Cholesterol and malaria sporozoites may use the same doorway into liver cells. A research group from Lisbon (MM Mota et al., Cell Host Microbe 2008, 4:3, 271-82) showed that the SR-BI receptor which is the entry port for HDL cholesterol also opens the door for malaria parasites. This establishes a first clear link between malaria infection and cholesterol uptake pathways, and a new intervention strategy against malaria. This was confirmed by CORDIS project 235864: uptake of exogenous cholesterol, rather than host cell de novo biosynthesis is important for the Plasmodium falciparum liver stage.
Human HDL cholesterol is also necessary for the in vitro culture of P falciparum (D Bansai et al., Lipids in Health and Disease, Biomed Central, 2005, 4-10).
In vivo Plasmodium continuously diverts cholesterol from hepatocytes and erythrocytes which leads to a lower cholesterol level in malaria patients ( UM Chuckwuocha et al., Asian Pac J Trop Med., 4-12, 2011, 993-4). A recent paper from Saudi Arabia ( IA Al-Omar et al., J Saud Chem Soc. 2010, 14, 83-89) showed that there is a significant inverse correlation between parasite count and cholesterol level in patients. The same effect on cholesterol depletion in murine malaria has been documented ( R Desowitz et al., J Parasitol 1968, 5-4, 1006-8).) And more recently in malaria infected children in Cameroon, malaria patients presented significantly lower levels of total cholesterol and HDL cholesterol than control. On the other hand LDL cholesterol and triglycerides were higher (H Tuekam, Maîtrise en Biochimie, Université de Douala, 2005). Several recent studies confirm the same trend. In summary it may be said that HDL is significantly decreased, LDL moderately but VLDL and tryglycerides are increased. HDL cholesterol is essential for a good health. Too low values lead to general weakness, prostration and finally to death.
The liver is also rich in glycogen, another nutrient for the parasites. Any perturbation in this power plant will put the parasite in a state of starvation and inhibit formation of merozoites. It had already been shown in 1957 that the liver glycogen of rats infected with Plasmodium berghei is depleted (T I Mercado et al., Am J Epidemiol. 66, 1957, 1-19).
Many medicinal plants are known for their hypolipidemic and hypoglycemic effect, essentially by the action of phytosterols. This is the case for Hypericum perforatum (St John’s Wort), Azaradirachta indica (Neem), Moringa olifeira, Hypoxis hemerocalliedea (African potato). Phytosterols present in these plants have a strong inhibitory effect on CYP 3A4 and 2B6, like those from grapefruit (P.S. Fasinu et al., Pharmaceutical Biology, 11 July 2013). This in turn may lead to a higher efficiency or even toxicity of other drugs and xenobiotics.
The cholesterol lowering effect of plant sterols was discovered first in the early 1950s. Plant sterols have the same structure as cholesterol but have a higher solubility and are more easily hydrolyzed than cholesterol. Their presence in the intestine thus adversely affects the solubilization and absorption of cholesterol from food. ( GV Vahouny et al., Am J Clinical Nutrit. 37, 1983, 805-809). This is the main reason phytosterols are added to margarine.

Phytosterols are well present in many vegetal oils (on the average 600 mg/100g), in nuts and kernels like avocado (250 mg/kg) and in most vegetables (50mg/kg) and fruits (20 mg/kg). Medicinal herbs contain higher concentrations than other plants. The Artemisia and Salvia genus contain around 200 mg of phytosterols per 100g of dry matter (Bianca Ivanescu, PhD Thesis IASI University Romania, 2010). A review of Chinese traditional herbal medicines confirms that they are rich in phytosterols . Some contain up to 280 mg/100g ( J Han et al., Wei Sheng Yan Jiu, 2009, 38-2, 188-91). Their concentration is often higher in stems and twigs than in leaves. The fact that phytosterols have been neglected in the fingerprint analysis of A annua and other medicinal plants is because they are difficult to analyze. They lack a good chromophore and thus require derivatization for measurement by HPLC-UV.
The claim that a diet rich in fibres may reduce the level of cholesterol could be related to the high concentration of phytosterols in fibres. And the claim that nut consumption reduces cardiovascular problems as documented in a recent paper ( S Rohmann et al., BMC Medicine 1013, 11: 165).
Corn stigmasterols are also used in conditions of high uric acid such as gout and some types of arthritis.. The same effect was noticed by GF (personal communication) for Artemisia annua stem infusions. It is also the case for the plant Costus igneus used in India as cure against urinary stones. The aqueous stem extract of this plant is very rich in stigmasterol and lupeol. All this is relevant to malaria because plasmodium generates pro-inflammatory uric acid.
Artemisia plants are known for their lipid-lowering effect, an effect similar to that obtained with statins. The aqueous extracts of Artemisia sieberi significantly lower total cholesterol, HDL, LDL and triglycerides in diabetic rats ( H Mansi et al., Intern J Pharmacol 3-6, 487-491, 2007). This is also the case for ethanolic extract of Artemisia princeps (UJ Jung et al., J Med Food, 2009, 12-6, 1238-44). A very recent paper from Korea (DW Lim et al., Molecules 2013, 18, 9241-9252) documents similar effects for Artemisia capillaris. Their results show that extracts of this plant enhance the lipid metabolism, reduce cholesterol, reduce hepatic lipid contents and the serum ALAT and ASAT levels.
The higher absorption of phytosterols from food leads to a depletion of erythrocyte membrane cholesterol and inhibits the “raft” function of cholesterol for the inward transport of nutrients to the vacuole of the parasite (S Frankland et al., Eukaryotic Cell, 2006, 849-860). Steroids and sterols may influence the biological membrane function of erythrocytes by modifying permeability, metabolite transport and energy metabolism. Research work from Colombia (ML Lopez et al., Mem Instit Oswaldo Cruz, 104, 683-688) shows that the majority of merozoites are unable to invade RBCs which have been treated with steroids of Solanum nudum.
In the erythrocytes it is likely that the parasite converts cholesterol into fragments and lipids which are activating the hemozoin formation (AU Orjih, Exp Biol Med. 2001, 226:8, 746-52). Phytosterols are able to replace cholesterol in cell membranes. Artemisia plants differ from other plants by a higher proportion of stigmasterol than beta-sitosterol which is the predominant sterol in all plants. Stigmasterol was found to modify the properties of cell membranes more strongly than beta-sisterol (Hac-Wydro K, Chem Phys lipids, 2010, 163:7, 689-97). It also inhibits the synthesis of cholesterol much more than beta-sisterol (J Clin Invest 2004, 114:6, 813-22). Phytosterols also inhibit isoprenylation of proteins in Plasmodium falciparum.

To survive the parasite needs to digest the proteins present in cholesterol. The need of intracellular parasites to retrieve nutrients and fulfill their energy needs is achieved by manipulating the host metabolism. Apicomplexa parasites like plasmodium have lost a substantial number of genes related to biosynthetic functions. Phytosterols may deactivate the parasite’s final digestive machinery, thus making it impossible to survive as it stops receiving nutrients.

Sept 2013
lutgenp@gms.lu

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