Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles

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.

Genomic control of inflammation in experimental atopic dermatitis

“…2 B), indicating a lack of NTCI’s general toxicity. This is consistent with the lack of apparent toxicity associated with long-term NTCI treatment in previous preclinical studies 10 , 17 . The lack of apparent toxicity of NTCI was also independently attested prior to the submission of the clinical trial protocol to the FDA (NCT04313400).…”

“…Its spectrum encompasses obesity, hyperglycemia, hyperlipidemia, fatty liver, atherosclerosis, and hypertension 40 . In the preclinical model of Metabolic Syndrome, due to the genetic ablation of the LDL receptor ( ldlr -/- ), combined with the Western Diet, NTCI controlled the metabolic hypersensitivity to a sublethal dose of LPS, a well-known inducer of microbial inflammation 17 . Thus, NTCI can also control AD, which is associated with inflammation caused by autoimmune, microbial, and metabolic inducers (see Fig.…”

“…Our cell-penetrating NTCI peptide, cSN50.1 (AAVALLPAVLLALLAPCVQRKRQKLMPC, 2986 Da) was synthesized as described elsewhere 17 . Briefly, the peptide chain was assembled through Solid Phase Peptide Synthesis (SPPS) according to standard Fmoc chemistry protocols using an automated peptide synthesizer FOCUS XC (AAPPTec, Louisville, KY).…”

“…Atopic dermatitis (AD)-like phenotype was induced in 8-week-old C57BL/6 female mice (The Jackson Laboratory) by topical application of the Vitamin D 3 analog, calcipotriol (MC903) 11 , 41 . The experimental groups (Mock Control, n = 3; MC903 Untreated, n = 5; MC903 + Saline, n = 5; and MC903 + cSN50.1, n = 5) were selected using a double blinded randomization method 17 .…”

Effects of sea buckthorn (Hippophae rhamnoides L.) on factors related to metabolic syndrome: A systematic review and meta‐analysis of randomized controlled trial

“…Hyperlipidemia is a sign of metabolic syndrome, and there is a close relationship between them (Liu et al, 2021). Therefore, we also analyzed TC and LDL‐c.…”