Cholesterol binds to bile acid micelles in the small intestine and is transported to the brush border of enterocytes, where it binds to Niemann-Pick C1-Like 1 (NPC1L1) and is delivered to the endocytic cycle compartment by clathrin-mediated endocytosis (22). NPC1L1 can be recycled back to the plasma membrane with the help of the LIM domain and actin-binding protein 1 (LIMA1), cell division cycle 42 (CDC42), the motor protein myosin Vb and actin filaments (23). Acyl-CoA:cholesterol acyltransferase (ACAT) then converts free cholesterol absorbed by enterocytes into cholesteryl esters (CEs), which are then incorporated into chylomicrons (CM), a triglyceride-rich lipoprotein type with a CEs-rich core and a single molecule of apolipoprotein B (ApoB)-48 on its surface (22). Microsomal triglyceride transfer protein (MTP) and apolipoprotein A (ApoA)-IV are essential for chylomicron assembly and size regulation (24). The endoplasmic reticulum (ER) then generates a pro-chylomicron transport vesicle (PCTV) to carry pro-chylomicrons to the Golgi apparatus (24). PCTV was translocated to the Golgi via the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex (24). Pro-chylomicrons mature into mature CM after the addition of Apo-I and enzymatic modification in the Golgi apparatus, after which they are transported to the basolateral membrane and released into the intercellular space by exocytosis (24). After entering the lamina propria from the intercellular space, CM enters the bloodstream via the thoracic duct or enters the liver through the portal vein (22). Figure 1 summarizes cholesterol absorption in the small intestine.

The liver is the principal organ for cholesterol synthesis, producing almost 50% of all generated cholesterol. In addition, almost all cells in the body can produce cholesterol (25). The synthesis of cholesterol is a complicated process with an expensive energy cost (23). In this section, we outlined the key metabolites and metabolic enzymes and the process of cholesterol synthesis in Figure 2 . Cholesterol is made and then release into the bloodstream as VLDL particles that is covered with ApoB100 (22).

Once CM and VLDL enter the circulation, the triglycerides in the core are digested into chylomicron fragments and LDL cholesterol by lipoprotein lipase (LPL) (22, 26). VLDL is hydrolyzed by LPL into intermediate-density lipoprotein (IDL), which is then converted into LDL via the hydrolysis of hepatic lipase (HL) (22). In addition, the triglycerides, CEs, and phospholipids in the HDL particles can be enriched to form CM and VLDL particles in the circulation by cholesteryl ester transfer proteins (CETP) and phospholipid transfer proteins (PLTP), which are accompanied by the interchange of apolipoproteins on the surface of lipoprotein particles (22, 27). Hereafter, chylomeric fragments and LDL particles are taken up by the low-density lipoprotein receptor (LDLR) and low-density lipoprotein receptor-related protein 1 (LRP1) in cells, while HDL particles are bound to the scavenger receptor type 1 (SR-B1) (26, 28). CEs are selectively delivered into cells when HDL particles attach to scavenger receptor type 1 (SR-B1) on the surface of hepatocytes. Following that, hormone-sensitive lipase (HSL) hydrolyzes CEs to liberate cholesterol (26). The processes of cholesterol transport and lipoprotein metabolism are shown in Figure 3 .

After being taken up by cells, the CEs carried by LDL particles are digested by lysosomal acid lipase to release free cholesterol, which is subsequently co-transferred to the lysosomal membrane by NPC intracellular cholesterol transporter 1 (NPC1), NPC2, and lysosome-associated membrane protein 2(LAMP2) and transported to other cell compartments (mainly ER, re-esterified to form CE) (23). HDL binds to SR-B1 on hepatocytes, delivering CEs from lipoproteins to the liver (23). Absorbed cholesterol in cells can be utilized to act as a component of biological membranes or to synthesize oxysterols (28). And in gonadal tissue, adrenal glands and brain cells, cholesterol can be used for steroid hormones (28). In the liver, most sterols are further metabolized into bile acids and bile salts, which are released into extracellular space through ATP Binding Cassette Subfamily B Member 11 (ABCB11) transporters to produce bile salt-phosphatidylcholine micelles for excretion (22). The metabolic processes of oxysterols, bile acids, and steroid hormones, as well as their roles in immune regulation, have been well described (29–32), and we will not go over them here.

While all cells can synthesize cholesterol, the vast majority are unable to catabolize it, forcing excess cholesterol to be excreted or stored in cytoplasmic lipid droplets (23). ACAT is in charge of esterifying free cholesterol to generate CEs that are stored in lipid droplets; the ATP-binding cassette (ABC) transporter superfamily is in charge of the efflux of intracellular cholesterol (23, 28). The ATP Binding Cassette Subfamily G Member 1 (ABCG1) is mainly expressed in macrophages and frequently dimerizes with another ABCG1 or ABCG4 to form a functional transport protein that primarily mediates cholesterol efflux to HDL, albumin, or other lipoproteins (23). ATP Binding Cassette Subfamily A Member 1 (ABCA1) is a ubiquitously expressed transporter that mediates cholesterol and phospholipid efflux to apoA-I, resulting in HDL formation. The ATP Binding Cassette Subfamily G Member 5 (ABCG5)/ATP Binding Cassette Subfamily G Member 8 (ABCG8) complex is primarily expressed in enterocyte brush boundaries and hepatocyte tubular membranes, where it mediates direct transintestinal cholesterol excretion (TICE) into the intestinal lumen or hepatic sterol efflux into bile (23, 24). The processes of cellular utilization, storage and efflux of cholesterol were summarized in Figure 3 .

Except for the intestine, NPC1L1 is also expressed in the liver, where it regulates hepatobiliary cholesterol excretion by transporting cholesterol in the bile to hepatocytes (33). NPC1L1 has been demonstrated to regulate inflammatory responses in vivo. NPC1L1 inhibition has been shown to reduce the production of pro-inflammatory proteins like β-catenin and p- extracellular signal-regulated kinase (ERK), cell proliferation and the inflammatory response in the intestine of mice (34). Ezetimibe, an NPC1L1-targeting inhibitor, can reduce the absorption of dietary and bile cholesterol, hence lowering lipid levels. Ezetimibe has been proven to effectively cut diet-induced circulating cholesterol levels while also inhibiting hepatic lipid build-up and lowering inflammatory factors such as high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1, IL-1β, IL-6, TNF-α, and oxidative stress (35–37). Experiments on the macrophage model demonstrated that ezetimibe could lead to an anti-inflammatory response by decreasing the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and blocking the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome- IL-1β pathway (38). Ezetimibe can also reduce oxidative stress and inflammatory responses mediated by caspase-1 and IL-1β through the AMP-activated protein kinase (AMPK)/NF-E2–related factor 2 (Nrf2)/thioredoxin interacting protein (TXNIP) pathway (39). And ezetimibe reduces monocyte chemoattractant protein 1-induced monocyte migration (40). Furthermore, ezetimibe was found to lower the frequency of Th17 and Th1 cells in RA mice and humans, as well as suppress the differentiation of Th17 cells and the production of pro-inflammatory molecules such as IL-1, IL-17, IFN-γ, TNF-α, and IL-6, thereby slowing the progression of RA (41). It has been documented that NPC1L1 could be affected by immune cells. Propionate produced by the gut microbiota suppressed intestinal NPC1L1 expression and corrected hyperlipidemia by increasing regulatory T-cell numbers and IL-10 (42). There is a scarcity of studies on ezetimibe in psoriasis. Only a clinical study revealed that ezetimibe was not linked to the risk of psoriasis (point estimates for ezetimibe revealed decreased psoriasis risk, but the null is included in the confidence intervals) (43). However, on the basis of the impacts of NPC1L1 on lipid metabolism, cell proliferation, and inflammation, we still hypothesize that inhibiting NPC1A1 may help relieve the symptoms of psoriasis, but further studies are needed to validate this hypothesis.

Imiquimod (IMQ)-treated psoriatic mice were paralleled by a clear dysregulation in hepatic lipid metabolism biomarkers as reflected by a decrease in HDL cholesterol and total cholesterol (125). Treatment with an anti-IL17A antibody led to a significant reversal of IMQ-induced changes in the liver biomarkers of lipid metabolism, whereas treatment with IL-17A further aggravated IMQ-induced changes in these biomarkers (125). Another study also showed that serum total cholesterol, and triglyceride in the high-fat-feed rats decreased after being injected with the IL-17 neutralizing antibody (126). LDL peroxidation results in oxidized low-density lipoprotein, often known as “ oxidized low-density lipoprotein (ox-LDL).” Ox-LDL is taken up by transmembrane scavenger receptors like SR-B1 and CD36, as well as by the lectin-like oxidized LDL receptor-1 (LOX-1) (127, 128). Excess oxygen metabolites overwhelm the antioxidant capacity of the organism, which is one of the important features of psoriasis (129). And the value of LDL in psoriasis is inconsistent and ambiguous; hence, ox-LDL, rather than LDL, is thought to be more meaningful to psoriasis (130). Consistent with this idea, psoriasis patients exhibit higher epidermal and serum ox-LDL levels, as well as autoantibodies against ox-LDL (15). Also, lipid peroxidation markers were associated with the severity and activity of psoriasis (129). Ox-LDL can engage in the progression of psoriasis through multiple mechanisms. On the one hand, ox-LDL could promote the production of IL-23 in dendritic cells (DCs), which is a key cytokine in the pathophysiology of psoriasis (131). A study by Chun-Ming Shih et al. also found that ox-LDL boosted IL-23 expression in TNF-α stimulated KCs via LOX-1, which is elevated and linked with the severity of the disease in psoriatic patients (127, 132). On the other hand, by over-expressing CD36 to uptake ox-LDL and form foam cells, psoriatic monocytes are more likely to evolve into M1 pro-inflammatory macrophages that produce psoriatic cytokines and raise the risk of cardiovascular disease comorbidity (128). In turn, pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which are increased in psoriasis, can activate LOX-1, promoting the uptake of ox-LDL by macrophages (133).

HDL takes part in reverse cholesterol transport (RCT) and possesses anti-inflammatory and antioxidant effects. HDL is responsible for the one-way transport of cholesterol to either apolipoprotein (apo) A-I via ABCA1, mature HDL particles via ABCG1, or the liver for metabolism by SR-B1 (134). By modulating the differentiation and function of immune cells such as macrophages, DCs, T cells, and B cells in vivo, HDL and apoA-1 can achieve an anti-inflammatory effect (135). Correspondingly, inflammation also drops the level of HDL, although the mechanism is still unknown. But it is believed that the decreased levels of HDL-associated proteins apoA-1, apoM, lecithin: cholesterol acyl transfer (LCAT), and CETP may all contribute (136). Besides, inflammation also impairs HDL’s capability to engage in RCT and protect LDL cholesterol from oxidation (136). In psoriasis, HDL cholesterol levels were decreased compared to healthy controls (15). Furthermore, the composition and function of HDL are altered in psoriasis, resulting in a decrease in cholesterol outflow and an impairment of anti-inflammatory and anti-oxidation of HDL (137). The expression of HDL-related proteins apoA-1, apoM, and apoF is reduced in psoriasis, whereas apoA-2, which plays a negative regulatory role, is increased (137). The activity of LACT, which is an important enzyme in the formation of HDL particles, was decreased in psoriasis patients, while its activity increased after biologics and other anti-psoriatic treatments in psoriasis patients (138). However, the change in HDL in psoriatic patients with anti-psoriatic medication appears paradoxical (27). Overall, HDL cholesterol efflux capability was impaired in psoriasis patients and was negatively correlated with the severity of the condition and the risk of cardiovascular comorbidities (27). As a result, anti-psoriatic medication focusing on HDL may benefit psoriatic patients suffering from cardiovascular issues.

Apolipoprotein E (apo E) is a multifunctional glycosylated protein with lipid transport immunomodulatory properties (139). Apo E shows a function of anti-inflammation and could intersect with inflammatory factors. Apo E promotes the transition of pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages (139). Compared to wild-type mice, mice that lack Apo E displayed a higher level of TNF-αand a higher mortality rate in response to the infection of pathogens (140). Additionally, Apo E deficiency may result in an increase in pro-inflammatory factors(IL-1, IL-2, IL-6, IFN-γand ICAM-1) and a decrease in anti-inflammatory factors (IL-4 and IL-10), promoting a Th1 immune response and an imbalance between Th17 cells and Regulatory T cells (Tregs) (139). Correspondingly, IFN-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated macrophages had a reduction of apoE (139). ApoE expression is reduced in psoriatic skin than in healthy controls, and restoration of apoE levels precedes clinical improvement (141). Furthermore, ApoE gene polymorphisms are correlated with psoriasis, indicating that ApoE may have a pathogenic role in psoriasis (142).

Previous biochemical and morphologic studies have revealed that LDL receptors (LDLR) activity is inversely related to the terminal differentiation of KCs (105). LDL receptor binding activity is only found in the basal cells and not in highly differentiated KCs in the normal epidermis (143). However, differentiated acanthocytes have higher LDLR activity in psoriasis (143). Similarly, LRP1 levels were higher in psoriasis patients, but anti-inflammatory molecules LRP5 and LRP6 were lower in psoriatic lesions and peripheral blood (144, 145).

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a target for decreasing LDL in the blood, sits at the crossroads of cholesterol metabolism and immune dysregulation. PCSK9 interactives with inflammation. PCSK9 regulates atherosclerotic plaque and inflammation in both lipid-dependent and lipid-independent ways, and its pro-inflammatory effect depends on two major signaling pathways: the principal pathway through which PCSK9 acts is the TLR4/NF-kB signaling pathway, while the LOX-1 axis is another linked pathway (146). PCSK9 activates NF-kB, which in turns activates TLR4 and LOX-1to generate TNF-α, IL-6, IL-1, and macrophage chemoattractant protein 1 (MCP-1) (146). In contrast, TNF-α and IL-6 can also stimulate the expression of PCSK9 (147). Recent studies showed that PCSK9 takes part in the development of psoriasis. Luan et al. described a direct link between PCSK9 and psoriasis for the first time (148). Their research found that psoriasis patients and IMQ-treated mice both had elevated PCSK9, and that inhibiting PCSK9 could lessen the inflammatory response in psoriasis by inhibiting KCs proliferation and the NF-κB pathway (148). According to their research, targeting PCSK9 may be a promising therapeutic for psoriasis. Garshick et al. further found that the level of PCSK9 was higher in psoriasis patients and K14-Rac1V12 -/+ psoriatic mice and was positively linked with the severity of psoriasis (149). Furthermore, they postulated that PCSK9 is connected with a higher atherosclerotic burden in psoriasis patients, and, using blood transcript analysis, they identified TNF, IL6, IL17A, and IL23 as PCSK9-related pathways (149). Another recently published study found that the PCSK9 single nucleotide polymorphism (SNP) rs662145 was a psoriasis susceptibility locus and that PCSK9 expression is negatively linked to IL-36, a critical driver of psoriasis (150). These findings will aid future studies into PCSK9’s role and mechanism in psoriasis. Only one clinical study explored the therapeutic effect of PCSK9 inhibitors (e.g., alirocumab) on psoriasis, and the results showed that inhibition of PCSK9 was associated with a reduced psoriasis risk (43).

CETP is a lipid transport protein in plasma that moves CEs from HDL to lipoproteins with apoB (151). CETP may have contradictory roles in inflammation. CETP gene gain-of-function mutations are associated with elevated IL-8 and decreased plasma HDL cholesterol levels (152). After LPS stimulation, macrophages from mice overexpressing CETP produced greater TNF-α, IL-1, IL-6, MCP-1, and IFN-γ, accompanied by a lower level of total and esterified cholesterol and a higher sepsis mortality rate (153). Nevertheless, several studies have shown that CEPT may have an anti-inflammatory role. CEPT may prevent macrophages with the M1 phenotype from switching to the M2 phenotype. CEPT also decreases the production of TNF-α, IL-6, and iNOS. And it also lowers the levels of free cholesterol and cell phagocytosis (144, 153, 154). Jun Chen et al. investigated the role of CETP in psoriasis. And the results showed that CETP-transgenic mice had significantly higher levels of IFN-γ, IL-1, IL-6, IL-17A, IL-17F, IL-22, and IL-23 in lesions and higher serum levels of TNF-α, IL-17, and IL-6 after IMQ-stimulation (151). The results of the study by Jun Chen et al. implied that CETP could aggravate psoriasis, and this could be CETP’s role in regulating inflammation and blood lipids. Then, we searched for studies that evaluated serum CETP concentrations in psoriasis patients. And the results showed that the expression of CETP was different. It was lower in some psoriatic patients, higher in others, and no difference in still others (155).

ACAT, also known as sterol O-acyltransferase (SOAT), is a therapeutic target for atherosclerosis; by converting cholesterol to CEs, ACAT is essential for maintaining cellular cholesterol homeostasis (156). ACAT1 is expressed by almost every cell in the body, whereas ACAT2 is mostly expressed by the liver and intestines but also by other tissues (156). ACAT has not yet been researched in psoriasis, but a series of studies show that ACAT has an interaction with immune cells and cytokines that exert an important role in psoriasis. ACAT1 can reduce cell proliferation and induce cell apoptosis (157). A bioinformatics study showed that the expression of ACAT1 was positively linked to macrophages, neutrophils, Th17 cells, and activated dendritic cells but negatively linked to plasmacytoid dendritic cells or natural killer cells (158). Inhibiting ACAT1 decreases the number of inflammatory monocytes and macrophages and changes them to an anti-inflammatory M2 phenotype, and blocking ACTA1 also decreases the expression of inflammatory factors like MCP-1 and CCL5/7 (159). Blocking ACAT1 with avasimibe significantly reduced serum TNF-αlevel in hypercholesterolemic patients (160). In turn, in monocytes and macrophages, IFN-γ, IL-1, TNF-α, and LPS can increase the expression of ACAT1 and promote the formation of CE-laden cells, and these effects are mostly dependent on the NF-B pathway (161, 162). ACAT inhibition is speculated to achieve its anti-inflammatory effect through increasing free cholesterol levels or altering oxysterol levels (156).

ABCG1 and ABCA1 are transport proteins that are related to RCT and have been used as therapeutic targets to lower lipids. ABCG1 was involved in epidermal differentiation. It was induced during KCs differentiation and was highly expressed in the outer epidermis (163). A series of studies have revealed that ABCG1- and ABCA1-mediated lipid transport has potent anti-inflammatory capabilities. ABCA1 and ABCG1 suppress innate immunological responses by reducing cholesterol-rich lipid raft membrane microdomains (164). ABCA1 preferentially lowered the FC concentration in lipid rafts and inhibited MyD88-dependent TLR translocation to lipid rafts, further reducing the inflammation in macrophages (165). Co-knockdown of ABCG1 and ABCA1 in DCs results in lipid buildup in DCs, which in turn leads to inflammasome activation, an increase of IL-1 and IL-18, and a phenotypic shift of T cells toward a Th1 phenotype (165). Moreover, the DC-ABCA1/G1 deficit increased GM-CSF-induced production of IL-23, IL-12, IL-17, and IL-6, as well as the differentiation of T cells into TH17 cells in splenic CD11c+ DCs (165). Inversely, inflammatory cytokines such as IL-17A, TNF, IL-1, and IL-10 can impact the expression levels of ABCA1 and ABCG1 in vivo ( 166–168). According to a review by John M. Gemery et al., ABCA1^-/- and ABCG1-/- mice have chronic stem cell mobilization, accelerated atherosclerosis, and increased IL-17, IL-23, and granulocyte colony-stimulating factor (G-CSF); in addition, elevated IL-17 and IL-23 in psoriasis might also induce stem cell upregulation/mobilization, which could hasten the establishment of atherosclerosis (169, 170). Hence, John M. Gemery et al. proposed that ABCA1 and ABCG1 may play a role in psoriasis via regulating inflammation, cholesterol metabolism, and cardiovascular complications. It is plausible to question if psoriasis-related inflammatory factors can interact with ABCG1 or ABCA1 to disrupt cholesterol metabolism and epidermal differentiation and exacerbate the inflammatory response.

ABCG5/8 is mostly expressed in the gut and liver, and it regulates TLR-induced inflammation (171). Additionally, inflammation adversely influences ABCG5/8 expression to impede cholesterol transport from the liver to the bile (172). Mice injected with IL-1β exhibited a time-dependent reduction in hepatic ABCG5 expression (173). Given a bile acid imbalance has been observed in patients with psoriasis and psoriatic arthritis (174) and the role of ABCG5/8 in the TICE, we speculate whether ABCG5 and ABCG8 play a role in the bile acid metabolism of psoriasis.