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. 2021 Dec 14;20(1):462.
doi: 10.1186/s12936-021-03999-2.

The association between acute fatty liver disease and nitric oxide during malaria in pregnancy

Mamoru Niikura  1 , Toshiyuki Fukutomi  2 , Shoichiro Mineo  3 , Jiro Mitobe  4 , Fumie Kobayashi  5
Affiliations

The association between acute fatty liver disease and nitric oxide during malaria in pregnancy

Mamoru Niikura et al. Malar J. .

Abstract

Background: Liver disease is a common feature of malaria in pregnancy, but its pathogenesis remains unclear.

Methods: To understand the pathogenesis of liver disease during malaria in pregnancy, comparative proteomic analysis of the liver in a mouse model of malaria in pregnancy was performed.

Results: Decreased levels of mitochondrial and peroxisomal proteins were observed in the livers of pregnant mice infected with the lethal rodent malaria parasite Plasmodium berghei strain NK65. By contrast, increased levels of perilipin-2, amyloid A-1, and interferon (IFN)-γ signalling pathway-related proteins were observed in the livers of infected pregnant mice, suggesting that IFN-γ signalling may contribute to the development of liver disease during malaria in pregnancy. IFN-γ signalling is a potential trigger of inducible nitric oxide synthase (iNOS) expression. Liver disease associated with microvesicular fatty infiltration and elevated liver enzymes in pregnant wild-type mice infected with malaria parasites was improved by iNOS deficiency.

Conclusions: In this study, a causative role of iNOS in liver disease associated with microvesicular fatty infiltration during malaria in pregnancy was demonstrated. These findings provide important insight for understanding the role of iNOS-mediated metabolic responses and the pathogenesis of high-risk liver diseases in pregnancy, such as acute fatty liver.

Keywords: Fatty liver; Liver disease; Malaria; Pregnancy; Proteome; iNOS.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Proteomic analysis of the liver of immunized pregnant mice infected with malaria parasites. A Schematic representation of immunisation, mating, and infection. Female C57BL/6 (B6) mice were injected with 1 × 104 erythrocytes infected with Plasmodium berghei XAT. Female mice were mated for 1 day and examined for the presence of a vaginal plug the following morning. Immunized mice with or without a vaginal plug were infected with 1 × 104 erythrocytes infected with lethal P. berghei NK65. B, C Venn diagrams of protein levels in the livers of unimmunized pregnant mice without infection (naïve pregnant mice), immunized pregnant mice infected with P. berghei NK65, and non-pregnant mice infected with P. berghei NK65 that changed twofold (B) or 0.5-fold (C) compared with uninfected non-pregnant mice. Data are representative of three independent experiments
Fig. 2
Fig. 2
Nitric oxide produced by inducible nitric oxide synthase (iNOS) is associated with microvesicular fatty infiltration. Immunized female wild-type (WT) and iNOS-knockout (KO) mice were infected intravenously with 1 × 104 erythrocytes infected with P. berghei NK65. A Course of parasitaemia. Closed and opened symbols indicate WT and iNOS-KO mice, respectively. Circles and triangles indicate pregnant and non-pregnant mice, respectively. Results are shown as the means ± standard deviation of three mice. The experiment was performed in triplicate with similar results. B–G Histological examination. Liver tissue staining with haematoxylin and eosin (B–D) and Sudan IV (E–G). Livers were obtained from mice on day 17 post-mating. B, E Immunized non-pregnant WT mice infected with P. berghei NK65. C, F Immunized pregnant WT mice infected with P. berghei NK65. D, G Immunized pregnant iNOS-KO mice infected with P. berghei NK65. Scale bar indicates 100 μm. Data are representative of six independent experiments
Fig. 3
Fig. 3
Biochemical examination of blood and cytokine levels. Samples of blood were obtained from immunized pregnant and non-pregnant mice infected with P. berghei NK65 on day 17 post-mating. Plasma aspartic aminotransferase (AST) (A), alanine aminotransferase (ALT) (B), glucose (GLU) (C), interferon (IFN)-γ (D), and interleukin (IL)-10 (E) levels are shown. Closed and opened symbols indicate wild-type (WT) and inducible nitric oxide synthase-knockout (iNOS-KO) mice, respectively. Non-pregnant indicate immunized non-pregnant WT and iNOS-KO mice infected with P. berghei NK65. Pregnant indicates immunized pregnant WT and iNOS-KO mice infected with P. berghei NK65. Asterisks indicate a statistically significant difference (P < 0.05 compared with immunized non-pregnant WT and iNOS-KO mice infected with P. berghei NK65; Tukey–Kramer and Dunnett test). Results are shown as the means ± standard deviation of three mice. Experiments were performed in triplicate with similar results
Fig. 4
Fig. 4
Inducible nitric oxide synthase (iNOS) may be involved in adverse pregnancy outcomes during malaria. A Pregnancy outcomes in uninfected pregnant wild-type (WT) mice and immunized pregnant WT and iNOS-knockout (KO) mice infected with P. berghei NK65. Number, survival rate, and weight of fetuses were measured at delivery. Experiments using three mice were performed in triplicate with similar results. Asterisks indicate a significant difference compared with the pregnancy period of uninfected pregnant WT mice (P < 0.05, Tukey–Kramer and Dunnett test). Dagger indicates a significant difference compared with the pregnancy period of immunized pregnant WT mice infected with P. berghei NK65. B–G Representative haematoxylin and eosin-stained placental sections are shown. Placentas were obtained from uninfected pregnant WT mice and immunized pregnant WT and iNOS-KO mice infected with P. berghei NK65 on day 17 post-mating. B–D Low magnification images of placentas. Scale bars indicate 200 μm. E–G Higher magnification of the labyrinth region. Scale bars indicate 100 μm. B, E Uninfected pregnant WT mice. C, F Immunized pregnant WT mice infected with P. berghei NK65. D, G Immunized pregnant iNOS-KO mice infected with P. berghei NK65. Data are representative of six independent experiments
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