Abstract
Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70–100% hyperlipidemic animals. Targeting importin β1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint.
Highlights
Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections
We found that the control of the nuclear transport checkpoint by nuclear transport modifier (NTM) peptide suppressed the expression of proinflammatory genes regulated by stress-responsive transcription factors (SRTFs), and metabolic genes controlled by Sterol Regulatory ElementBinding Proteins (SREBPs) as well as ChREBPs21
Animals treated with NTMs targeting importin α5 (Imp α5)-mediated nuclear import, i.e. cSN50.1 and cSN50.1α peptides, displayed inhibition of glycogenolysis, suppressed Vascular Cell Adhesion Molecule (VCAM)-1 expression in endothelial cells, and the arrest of neutrophil trafficking in the liver and lungs, In striking contrast, short-term administration of importin β1 (Imp β1)-selective NTM, cSN50.1β peptide, was ineffective in protecting organs from devastating action of LPS shock in hyperlipidemic mice (Fig. 7), consistent with the survival data (Fig. 6A). These results support the concept that hyperlipidemia, the key component of Metabolic Syndrome (MetS), increases the susceptibility to lethal microbial inflammation. They demonstrate that selective inhibition of Imp α5-mediated nuclear transport of SRTFs and Imp β1-mediated nuclear transport of metabolic transcription factors (MTFs) counteracts lethal microbial inflammation in hyperlipidemic animals
Summary
Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. Infections in patients with MetS-linked underlying diseases of the cardiovascular, respiratory, pancreatic (diabetes), hepatobiliary, and renal systems, include the recent outbreaks of COVID-19 They evolve into a more severe and difficult to control stage of microbial inflammation[4,5,6,7,8,9]. These patients are more vulnerable to the fatal outcomes of acute respiratory distress syndrome (ARDS), septic cardiomyopathy, microvascular thrombosis (known as Disseminated Intravascular Coagulation), and Acute Kidney Injury. Hyperlipidemia increases Endoplasmic Reticulum (ER) stress causing Caspase 2-induced processing of metabolic transcription factors (MTFs) S REBPs19 (see Fig. S1)
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