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Review
. 2021 Apr 12:9:654913.
doi: 10.3389/fcell.2021.654913. eCollection 2021.

Metabolic Syndrome and Autophagy: Focus on HMGB1 Protein

Vincenza Frisardi  1 , Carmela Matrone  2 , Maria Elisabeth Street  3
Affiliations
Review

Metabolic Syndrome and Autophagy: Focus on HMGB1 Protein

Vincenza Frisardi et al. Front Cell Dev Biol. .

Abstract

Metabolic syndrome (MetS) affects the population worldwide and results from several factors such as genetic background, environment and lifestyle. In recent years, an interplay among autophagy, metabolism, and metabolic disorders has become apparent. Defects in the autophagy machinery are associated with the dysfunction of many tissues/organs regulating metabolism. Metabolic hormones and nutrients regulate, in turn, the autophagy mechanism. Autophagy is a housekeeping stress-induced degradation process that ensures cellular homeostasis. High mobility group box 1 (HMGB1) is a highly conserved nuclear protein with a nuclear and extracellular role that functions as an extracellular signaling molecule under specific conditions. Several studies have shown that HMGB1 is a critical regulator of autophagy VSports手机版. This mini-review focuses on the involvement of HMGB1 protein in the interplay between autophagy and MetS, emphasizing its potential role as a promising biomarker candidate for the early stage of MetS or disease's therapeutic target. .

Keywords: HMBG1; autophagy; cellular homeostasis; insulin resistance; metabolic syndrome; oxidative stress V体育安卓版. .

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

"V体育官网入口" Figures

FIGURE 1
FIGURE 1
Schematic representation of macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. (A) In macroautophagy, cargos are sequestered by phagophores, which elongate and form a double membranous structure, the autophagosome. Autophagosomes then fuse with the lysosome to form autolysosomes. (1) Nucleation consists of the formation of the phagophore. A class III of phosphoinositide 3-kinases (PI3K) complex consisting of beclin 1 (BCN1), Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4), UV radiation resistance-associated gene protein (UVRAG), and Autophagy And Beclin 1 Regulator 1 (AMBRA1) is required for phagophore formation. (2) Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3) complex anchors to the membrane via a phosphoethanolamine (PE) anchor (LC3-II) and triggers the elongation. (3) The phagophore sequesters cytosolic cargo and forms a double-membranous vesicle, the autophagosome. (4) Maturation, the completed autophagosome undergoes multiple maturation steps. (5) Docking and fusion, the autophagosome is released into the lysosome/autolysosome to be degraded by lysosomal hydrolases or to become available for re-usage (6). (B) In CMA (left), substrate proteins that can be damaged by various factors, such as reactive oxygen species (ROS), bind the Lysosomial- Heat shock cognate 71 kDa protein (Lys-Hsc70) chaperone through a specific amino acid sequence (the KFERQ motif) and are transported across the lysosomal membrane for degradation via interaction with lysosomal-associated membrane protein 2A (Lamp2A) proteins. (C) Microautophagy (right) involves the direct engulfment of portions of the cytoplasm into lysosomes.
FIGURE 2
FIGURE 2
The schematic interplay among HMBG1, autophagy, and Metabolic Syndrome. HMGB1, High mobility group box 1; c23, c46, c106, cysteine at 23, 46, 106 position; ROS, reactive oxygen species; BCN1, Beclin-1; ATG, autophagy-related genes; Neuroendocrine hormones F/S, fasting/starvation; mTOR, mammalian target of rapamycin; NF-κb, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukines; TNF-α, tumor necrosis factor-alpha; p53, protein 53; p73, protein 73; RB, retinoblastoma protein; Rel/Nf-κB, member of Rel/Nf-κB family; ER, estrogen receptor; C, caspases, non-canonical inflammasome; RAGE, advanced glycosylation end product-specific receptor; TLR2 and TLR4, Toll-like Receptor 2 and 4; TIM-3, T-cell immunoglobulin mucin-3; CXCR4, chemokine C-X-C motif receptor 4; Mac-1, macrophage-1 antigen; CD138, syndecan-1; CD24, cluster of differentiation 24; M, macrophages; IR, Insulin Resistance; AT, Adipose Tissue. HMGB1 functions as a Damage Associated Molecular Pattern (DAMP) protein in the extracellular space. A mixture of different HMBG1 isoforms (CH = reduced form; SH2: disulfide HMBG1, SH3 oxidized form) in the extracellular space activates different pathway signaling. As the disulfide HMBG1 is responsible for autophagy activation, which counteracts the metabolic consequences of MetS. During an overload of food nutrients, there is an increase in ROS. The oxidative environment modifies the Reduced/oxidized HMBG1 ratio, increasing the dysregulation in Insulin/mTOR signaling, which blocks the autophagy machinery. It follows an increased risk for the “unhealthy” obese to develop MetS complications due to an unbalance among the downstream IR pathway, chronic inflammatory pattern and inability to counteract metabolic derangements via autophagy machinery disruption. HMGB1 is an autophagic regulator that mediates stress response: in normal condition, cytosolic HMGB1 as BECN1-binding protein induces autophagy. Extracellular HMGB1 binds RAGE, which inhibits mTOR and promotes autophagy. In chronic obesity and switching from insulin-sensitive to IR state, change in oxidative environment modifies the HMBG1 activity altering its inducer role in autophagy. In the nucleus, HMBG1 interact with and enhances the activities of number of transcription factors, including p53, p73, RB, Rel/Nf-κB, and ER. Once released, HMBG1 binds to various receptors to activate DAMP signaling involved in multiple cellular processes. Inflammasomes are a cytosolic multiprotein complex formation that are recruited by external pathogen and/or internal stimuli. Chronic inflammasomes lead to chronic inflammatory status increasing the risk of clinical consequences of MetS. HMGB1 triggers C (Caspase-4/caspase-5) which are components of the “non-canonical inflammasome” with cytokines release and induction of pyroptosis (a kind of proinflammatory cell death combining features of both apoptosis and necrosis).
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