Abstract
Malaria is a major parasitic disease of humans and is a health public problem that affects more than 100 countries. In 2017, it caused nearly half a million deaths out of 219 million infections. Malaria is caused by the protozoan parasites of the genus Plasmodium and is transmitted by female mosquitoes of the genus Anopheles. Once in the bloodstream, Plasmodium merozoites invade erythrocytes and proliferate until the cells lyses and release new parasites that invade other erythrocytes. Remarkably, they can manipulate the vertebrate host’s lipid metabolism pathways, since they cannot synthesize lipid classes that are essential for their development and replication. In this study, we show that mice infected with Plasmodium chabaudi present a completely different plasma profile from control mice, with marked hyperproteinemia, hypertriglyceridemia, hypoglycemia, and hypocholesterolemia. In addition, white adipose and hepatic tissue and analyses from infected animals revealed the accumulation of triacylglycerol in both tissues and free fatty acids and free cholesterol in the liver. Hepatic mRNA and protein expression of key enzymes and transcription factors involved in lipid metabolism were also altered by P. chabaudi infection, leading to a lipogenic state. The enzyme 5′ AMP-activated protein kinase (AMPK), a master regulator of cell energetic metabolism, was also modulated by the parasite, which reduced AMPK phosphorylation levels upon infection. Pretreatment with metformin for 21 days followed by infection with P. chabaudi was effective in preventing infection of mice and also lowered the hepatic accumulation of lipids while activating AMPK. Together, these results provide new and important information on the specific molecular mechanisms induced by the malaria parasite to regulate hepatic lipid metabolism in order to facilitate its development, proliferation, and lifespan in its vertebrate host.
Highlights
Malaria is a major parasitic disease of humans and is a health public problem that affects more than 100 countries
Considering that the metabolic consequences and the specific hepatic molecular mechanisms underlying the pathogenesis of malaria are still unclear, we aimed to investigate changes in lipid metabolism during Plasmodium chabaudi infection in mice in order to better understand their importance to the host–parasite interaction and to the outcome of the infection
We demonstrated that AMPK phosphorylation levels decrease significantly upon infection (p < 0.05; Fig. 4A and Supplementary S1A), which is accompanied by decreased phosphorylation of acetyl-CoA carboxylase (ACC), the transcription factor sterol regulatory element binding protein-1c (SREBP-1c), and PPARα (p < 0.001; Fig. 4B,C,F, respectively and Supplementary S1B,C,F)
Summary
Malaria is a major parasitic disease of humans and is a health public problem that affects more than 100 countries. Pretreatment with metformin for 21 days followed by infection with P. chabaudi was effective in preventing infection of mice and lowered the hepatic accumulation of lipids while activating AMPK Together, these results provide new and important information on the specific molecular mechanisms induced by the malaria parasite to regulate hepatic lipid metabolism in order to facilitate its development, proliferation, and lifespan in its vertebrate host. There are some events, that are fundamental to malarial pathogenesis: (1) the massive release of proinflammatory cytokines induced by the rupture of infected erythrocytes, (2) the adhesion of infected red blood cells (RBCs) in capillaries, and (3) the rupture and removal of infected RBCs by splenic macrophages Together, these phenomena are responsible for the major syndromes associated with malaria, such as systemic inflammation, anemia, metabolic acidosis, and placental and cerebral malaria[6,7,8]. The Inhibition of ACC stimulates fatty acids’ oxidation through a decrease of malonyl-CoA17,18, leading to an increased activity of carnitine palmitoyl transferase 1 (CPT1)[19]
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