The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

Abstract

Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.

Keywords: IBD - inflammatory bowel disease; NLRP3 inflammasome; diet phytochemicals; inflammasome; intracellular cholesterol accumulation; mitochondrial dysfunction.

Figure 1

Absorption and re-esterification of exogenous and endogenous lipids and sterols by intestinal epithelial cells. Dietary cholesterol, MAGs, and free FA, inside of mixed micelles reach the enterocytes. A selective cholesterol absorption results from regulated mechanisms differentiating from other micellar lipid components. The cholesterol transport from micelles, contacting the intestinal cell microvilli, is carried out by NPCL1 through cholesterol-regulated clathrin-mediated endocytosis. Once in the enterocyte, the TG re-esterification is carried out by two enzymes: MGAT and DGAT. Both incorporate FA, the first to a MAG, while the second to a DAG, resulting in TG formation. Likewise, free cholesterol is re-esterified with FA by the ACAT. Endogenous and exogenous FA are used in re-esterification, with the TG produced by re-esterification, leaving the enterocytes for their distribution to different tissues. Therefore, in the enterocyte, re-esterified TG and cholesterol, as well as phospholipids and apo B-48, form chylomicrons. These are secreted from the basolateral cell region to the lymphatic vessels and afterward into the circulation. MAGs, Monoacylglycerols; NPCL1, Niemann-Pick C1 Like 1; TG, Triacylglyceride; MGAT, Monoacylglycerol acyltransferase DGAT, Diacylglyceride acyltransferase; FA, Fatty acids; DAG, Diacylglycerol; ACAT, Acyl-CoA-cholesterol-acyltransferase.. This figure was created with BioRender.com.

Figure 2

Alterations in cholesterol dynamics and mitochondrial dysfunction in IBD mucosa. In (A), inflamed intestinal mucosa shows enterocytes and macrophages have impaired transport cholesterol in IBD, with increased LDL-R, NPC1, and StADR3 allowing cholesterol influx and decreased ABCG1, SR-BI, and LXR preventing cholesterol efflux. In (B), also, mitochondria lose their function, promoting mitochondrial dysfunction, characterized by decreased expression of mitochondrial and nuclear genes associated with ETC and ATP synthase, NAD⁺ depletion, reduced levels of TCA cycle intermediates, reduction of Δψm, increased mtROS production, mitochondrial morphological changes with increased of DRP1 expression to regulate mitophagy and mitochondrial fission, and release of mtDNA. An imbalance in cholesterol traffic and mitochondrial function can activate NLRP3 inflammasome and promote inflammation of intestine mucosa, such as cholesterol, mtDNA, mtROS, and cardiolipin. However, there are no studies linking cardiolipin to IBD. IBD, Inflammatory Bowel Disease; LDL-R, low-density lipoprotein receptor; NPC1, Niemann–Pick C1 protein cholesterol transporter; StADR3, Steroidogenic acute regulatory; ABCG1, ATP Binding Cassette Subfamily G Member 1; SR-BI, scavenger receptor class B type I; LXR, Liver X receptor; ETC, Electron transport chain; TCA, Tricarboxylic acid; Δψm, mitochondrial membrane potential; mtROS, mitochondrial reactive oxygen species; DRP1, dynamin-related protein 1; mtDNA, mitochondrial DNA; NLRP3, NLR (Nod-like receptor) family pyrin domain containing 3. This figure was created with BioRender.com.

Figure 3

Dietary compounds and activation of Nrf2 pathway preventing inflammation. dietary compounds, such as polyphenols, prevent oxidative stress, mitochondrial dysfunction, and intracellular cholesterol trafficking via Nrf2 signaling. Sequestered in the cytoplasm by Keap1, Nrf2 is inactive, however, when phosphorylated by polyphenols, it can be released from Keap1, translocate to the nucleus, and form a heterodimer with small Maf proteins. This allows cellular protection and adaptive responses through the cytoprotective gene expression (1A), thus suppressing the inflammation (1B). Additionally, phytochemicals acting as prebiotics promote a healthy microbiota, which ensures an accurate amount of bacterial metabolites, enhancing the epithelial barrier function and reducing the inflammatory response (2). Nrf2, Nuclear erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein1. This figure was created with BioRender.com.

Figure 4

Schematic model showing the effects of phytochemicals on lipid metabolism, increase of PPAR-γ SIRT1, PGC-1α, and UCP1 expression. Polyphenols can deacetylate PPAR-γ and PRDM16, promoting the UCP1, PPAR-γ, SIRT1, and PGC-1α overexpression. On the other hand, via TRPV1, polyphenols can increase SIRT1 expression, and through β3-AR activation, increase cAMP levels, activating MAPKs pathway, resulting in TG hydrolysis, FA oxidation, and increased mitochondrial UCP1 transcription and activity. PPAR-γ, Peroxisome proliferator- activated receptor-gamma; SIRT1, Sirtuin 1; PGC-1α, Peroxisome proliferator- activated receptor-alpha; PRDM16, PR domaing containing 16; UCP1, Uncoupling protein 1; TRPV1, Transient receptor potential vanilloid 1; β3-AR, β3-adrenergic receptor; TG, Triacylglyceride; FA, Fatty acid. This figure was created with BioRender.com.