Preprint Article Version 1 This version is not peer-reviewed

Gender-Related Differences in Hepatic Inflammation, Lipid Metabolism and Mitochondrial Function Following Early Lipopolysaccharide Exposure in Epileptic WAG/Rij Rats

Stefania Melini
,
Giovanna Trinchese
,
Adriano Lama
,
Fabiano Cimmino
,
Filomena Del Piano
,
Federica Comella
,
Nicola Opallo
,
Antonio Leo
,
Rita Citraro
,
Luigia Trabace
,
Giuseppina Mattace Raso
,
Claudio Pirozzi
* ,
Maria Pina Mollica
,
Rosaria Meli
Version 1 : Received: 4 July 2024 / Approved: 4 July 2024 / Online: 4 July 2024 (14:41:01 CEST)

How to cite: Melini, S.; Trinchese, G.; Lama, A.; Cimmino, F.; Del Piano, F.; Comella, F.; Opallo, N.; Leo, A.; Citraro, R.; Trabace, L.; Mattace Raso, G.; Pirozzi, C.; Mollica, M. P.; Meli, R. Gender-Related Differences in Hepatic Inflammation, Lipid Metabolism and Mitochondrial Function Following Early Lipopolysaccharide Exposure in Epileptic WAG/Rij Rats. Preprints 2024, 2024070440. https://doi.org/10.20944/preprints202407.0440.v1 Melini, S.; Trinchese, G.; Lama, A.; Cimmino, F.; Del Piano, F.; Comella, F.; Opallo, N.; Leo, A.; Citraro, R.; Trabace, L.; Mattace Raso, G.; Pirozzi, C.; Mollica, M. P.; Meli, R. Gender-Related Differences in Hepatic Inflammation, Lipid Metabolism and Mitochondrial Function Following Early Lipopolysaccharide Exposure in Epileptic WAG/Rij Rats. Preprints 2024, 2024070440. https://doi.org/10.20944/preprints202407.0440.v1

Abstract

Epilepsy is a non-communicable neurological disease characterized by abnormal brain activity with conceivable peripheral implications. Few studies examine the role of peripheral and brain inflammation in the relationship between seizure predisposition and nonalcoholic fatty liver disease. Severe early-life infections leading to sepsis results in increased inflammation that can aggravate epilepsy and hepatic damage progression both associated with increased odds for hospital admissions in epileptic patients. Here, we examined the effect of early LPS challenge (1 mg/kg, i.p. at post-natal day3, PND3) in inducing hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45), evaluating the intra- and inter-gender differences on systemic and liver inflammation, hepatic lipid dysmetabolism and oxidative damage associated to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Early LPS challenge induced a major inflammatory and immune response in male epileptic rats than females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-insulted females showed a marked alteration in hepatic metabolic and lipid profile and the reduction in mitochondrial fatty acid oxidation. The two different gender-related mechanisms of LPS-induced liver injury converge in mitochondrial oxidative damage with intensified ROS production in both sexes, that notably induced a compensatory increase in antioxidant defense only in females. Our study with a translational potential points out that early postnatal infections predispose epileptic rats to develop or worsen hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment.

Keywords

genetic animal model; epilepsy; mitochondrial bioenergetics; oxidative damage; sex-dependent alterations; neonatal infections

Subject

Medicine and Pharmacology, Endocrinology and Metabolism

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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