Skip to main content

Roles of lipid metabolism in keloid development


Keloids are common cutaneous pathological scars that are characterised by the histological accumulation of fibroblasts, collagen fibres, and clinically significant invasive growth. Although increasing lines of research on keloids have revealed genetic and environmental factors that contribute to their formation, the etiology of these scars remains unclear. Several studies have suggested the involvement of lipid metabolism, from a nutritional point of view. However, the role that lipid metabolism plays in the pathogenesis and progression of keloids has not previously been reviewed. The progress that has been made in understanding the roles of the pro- and anti-inflammatory lipid mediators in inflammation, and how they relate to the formation and progression of keloids, is also outlined. In particular, the possible relationships between mechanotransduction and lipid metabolites in keloids are explored. Mechanotransduction is the process by which physical forces are converted into biochemical signals that are then integrated into cellular responses. It is possible that lipid rafts and caveolae provide the location of lipid signaling and interactions between these signaling pathways and mechanotransduction. Moreover, interactions between lipid signaling pathway molecules and mechanotransduction molecules have been observed. A better understanding of the lipid profile changes and the functional roles lipid metabolism plays in keloids will help to identify target molecules for the development of novel interventions that can prevent, reduce, or even reverse pathological scar formation and/or progression.


Keloids are a type of cutaneous pathological scar. Regarding their clinical characteristics, they usually “invade” into the neighboring healthy skin with a leading edge that is often erythematous and pruritic, and they are difficult to treat. In terms of their pathological characteristics, they exhibit the accumulation of fibroblasts and collagen fibres that are hyalinised and eosinophilic [1]; as such, they can be considered as a fibroproliferative disorder of the skin [2]. Increasing research into the etiology of keloids has mainly centered on genetic factors [3] and local factors, such as wound tension [4], sebum secretion [5], and neurogenic inflammation [6]. However, several studies by Louw have suggested, mainly from the nutritional point of view, that essential fatty acids may be involved in the formation and progression of keloids [710], which has galvanised research into the contribution of nutrition in keloid development and progression. However, the roles that lipid metabolism may play in keloid pathogenesis have not previously been reviewed.

Lipids mainly constitute the storage fat triglyceride and the lipoids. The lipoids include a wide range of functionally-active molecules, such as phospholipids, glycolipids, and cholesterol. In the skin, they are mainly found in biomembrane structures (e.g., phospholipids) and the stratum corneum (e.g., ceramides), where they serve as membrane constituents and provide secondary messengers. More importantly, they are functionally involved in local inflammation and intracellular signal transduction. A better understanding of the lipid profile changes and functional roles of lipid metabolism in keloids will help to identify target molecules for the development of novel interventions that can prevent, reduce, or even reverse pathological scar formation and/or progression.

Constitutional changes in lipid profiles in keloid

When comparing the mean concentrations of lipids, the ratio of triglycerides in keloidal skin is 60% of that in normal skin, although it has similar ratio of cholesterol and fatty acids. The cholesterol ester and wax ester levels are reduced to 67% and 20% of the levels in normal skin, respectively [11]. This may reflect changes in the mechanisms that cause these esters to accumulate in the skin, namely their transfer from the dermis, adipose tissue and serum, their synthesis in the epidermis, and their modification by bacterial enzymes [11, 12]. In relation to this, patients with keloids have been found to consume higher levels of dietary linoleic acid (LA) and arachidonic acid (AA) than recommended (7–11 g/d), and they also consume α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) at levels below the recommended 1.1–1.5 g/d [9]. Moreover, keloids bear higher levels of AA than the skin of keloid-prone and non-keloid-prone patients [10]. It may result from (1) excessive dietary intake of AA itself and its precursor LA by patients with keloids, (2) the activated phospholipase A2 (PLA2) for AA release from the membrane pool, and (3) the infiltration of lymphocytes and cytokine secretion in the keloid edges which deplete inflammatory competitor of EPA [10]. Moreover, topical glucocorticosteroids, which are often used to treat keloids, can inhibit the synthesis in the epidermis and cultured keratinocytes of the three key stratum corneum lipids, namely cholesterol, fatty acids, and ceramides. Such epidermal lipid synthesis inhibition decreases the levels of lipid precursors for lamellar body formation and lamellar bilayer generation [13]. This observation supports the notion that changes in the lipid composition of keloids may be associated with their progression.

Relationship between lipid metabolism and inflammation in keloids

Keloids are clinically characterized by chronic inflammation of the leading edges during their invasion into the neighboring healthy skin. This is supported by the presence of infiltrating inflammatory cells on histology [2]. It has been suggested that this prolonged, active inflammatory reaction is due to cyclical skin tension, which stimulates mechanotransduction pathways [14]; it may also induce the production of neuropeptides that promote neurogenic inflammation pathways [6]. Recently, it was suggested that another etiological factor of keloids is altered lipid metabolism, particularly the metabolic processes that relate to essential fatty acids. It is possible that these alterations may promote the inflammatory reaction in keloids.

High levels of AA are a prominent characteristic of keloids [10]. AA is the source of several downstream products, including the classic eicosanoids: namely, leukotrienes (LTs), such as LTB4; prostanoids of prostaglandins (PGs), such as PGE2; prostacyclins, such as PGI; and thromboxanes (TXs) (Figure 1). These eicosanoids are generally considered to be pro-inflammatory modulators. However, AA is also the source of the non-classic eicosanoids, called lipoxins (LXs), which serve to downregulate inflammation (Figure 1). Notably, although PGE2 is classically thought to be pro-inflammatory, it is increasingly being realized that it can act in an anti-inflammatory fashion as well, as it inhibits the production of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [15] and improves the production of the anti-inflammatory lipoxins by inducing 15-lipoxygenase (15-LOX) [16, 17]. This is in accordance with the fact that, compared to normal human dermal fibroblasts, keloid-derived fibroblasts (KFs) have a diminished capacity to produce PGE2[18]. Moreover, KFs produce less PGE2 in response to macrophage migration inhibitory factor (MIF) and have lower E prostanoid receptor 2 levels [19]. Given that PGE2 enhances MMP-1 expression [20], the reduced PGE2 levels in keloids may be responsible for the decreased MMP-1 production by keloids and their subsequent accumulation of extracellular matrix (ECM). Another lipid mediator, called cyclopentenone prostaglandin 15-deoxy- Δ12,14-prostaglandin J2 (15d-PGJ2), also appears to have both pro-inflammatory and anti-inflammatory activities. These activities are dependent on its concentration: at low concentrations, it enhances eotaxin-induced chemotaxis in eosinophils; but at high concentrations, it inhibits eosinophil survival by inducing apoptosis [21]. To our knowledge, little is known about the roles played in keloids by other products of AA metabolism, such as LT, PGI, and TX.

Figure 1
figure 1

Overview of the pro- and anti-inflammatory lipid modulators that are generated by lipid metabolism. Lipid metabolism produces not only the classical pro-inflammatory lipid modulators, namely, the prostaglandins, leukotrienes, and thromboxanes, it also generates anti-inflammatory lipid modulators, namely, lipoxins, protectins, and resolvins (in dashed boxes). The possibility that keloid formation may be promoted by imbalances between the pro- and anti-inflammatory lipid modulators is attracting increasing interest in keloid research. (AA: arachidonic acid; ALA:α-linolenic acid; COX: cycloxygenase; DGLA: dihomo-γ-linolenic acid; DHA: docosahexaenoic acid; ETA: eicosatrienoic acid; EPA: eicosapentaenoic acid; GLA: γ-linolenic acid; HETrE: hydroxyeicosatrienoic acid; HPEPE: hydroperoxyeicosapentaenoic acid; HPETE; hydroperoxyeicosatetraenoic acid; HEPE: hydroxyeicosapentaenoic acid; HETE: hydroxyeicosatetraenoic acid;LA: linoleic acid;LT: leukotriene; LOX: lipoxygenase; LX: lipoxin; NPD1: neuroprotectin D1; PG: prostaglandin;PLA2: phospholipase A2; SA: stearidonic acid; TX: thromboxane; Rv: resolvin).

Given that AA has pro-inflammatory effects and EPA and its downstream product, DHA, can inhibit the production of inflammatory cytokines, such as IL-6 or TNF-α [2224], Louw postulated that keloids may be treated by modulating the membrane FA composition, namely to reduce AA levels by supplementing the diet with GLA, DGLA, and EPA; it was proposed that this would restore the levels of AA precursors and inflammatory competitors and reduce the excessive release of AA [10]. This notion was supported by the fact that snake oil, which has high levels of LA, inhibits the growth of human KFs in vitro[25]. Moreover, this traditional African medicine, when consumed, both prevents and treats keloids [10].

Given that keloids, as fibroproliferative disorders, are to some extent the product of an imbalance between pro-and anti-inflammatory processes, attention should be paid to the “good” lipid mediators, namely, those that resolve and antagonize inflammation and even show antifibrotic effects, with the help of 5-LOX and 15-LOX. These “good” mediators include the LXs, protectin Ds (PDs), and resolvins (Rvs). Of these, the AA- and EPA-derived LXs and the aspirin-triggered LXs (ATLs) have endogenous anti-inflammatory, proresolving and anti-fibrotic functions [26, 27]. Supporting evidence comes from studies on experimental dermal fibrosis: in this model, 15-LOX and its LX metabolites play a prominent anti-fibrotic role [28]. LXA4 and ATLa also attenuate experimental renal [29] and pulmonary [27] fibrosis, respectively. Similarly, the Rv and PD lipid mediators possess potent local anti-inflammatory and resolution properties [30]. However, although they can inhibit fibrosis in organs such as the kidney [31], little is known about their influence in skin and keloids. The mechanisms that cause switching between the lipid mediator classes, namely, from the generation of pro-inflammatory PGs and LTs to the production of anti-inflammatory LXs, PDs, and Rvs, also remain to be clarified. This information will help to identify the pathways that can be targeted to inhibit or prevent keloids.

Relationship between lipid-derived secondary messengers and keloids

Lipids are not only constituents of the skin and can act as pro- and anti- inflammatory factors, they are also the source of secondary messengers that can influence the cellular events that are responsible for the development of keloids. These secondary messengers include diacylglycerol (DAG), ceramide and AA. In terms of keloid development, the most significant of these molecules is DAG. DAG binds to the cysteine-rich domains of protein kinase C (PKC) [32] and high levels of DAG correlate with persistent activation of PKC [33], which has been shown to contribute to the proliferation of fibroblasts in keloids [10]. Another important molecule in keloid development is ceramide, whose structure is similar to that of DAG. Ceramide is a lipid secondary messenger that is derived from cell membrane sphingomyelin and influences apoptosis pathways that are induced by stimuli such as Fas antigen [34, 35]. Thus, ceramide mediates extracellular signals. Compared to normal dermal fibroblasts, KFs appear to be resistant to ceramide-induced apoptosis because they over-express insulin-like growth factor I (IGF-I) receptor [36]. It may also be that Fas-mediated signals are not transduced to ceramide in keloids and ceramide is not activated in anti-Fas-stimulated KFs [37]. With regard to AA, although it produces inflammatory factors and has long been known to participate in messenger systems that involve kinases, such as PKC, PKA, and mitogen-activated protein kinase (MAPK) [38], whether it can serve in KFs as secondary messengers remains unclear. Moreover, little seems to be known about the keloid-forming roles of other possible lipid-derived second messengers, such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and inositol-1,4,5-triphosphate (IP3).

Interactions between lipids and mechanotransduction in keloids

Lipids are essential components of the membrane, which is the interface between the extracellular and intracellular compartments. This fact, together with the fact that lipids and their endogenous metabolites provides pro- and anti-inflammatory factors and secondary messengers, strongly supports the notion that lipids may influence the intracellular signaling pathways in keloids. Keloids are fibroproliferative skin disorders that appear increasingly to have a close relationship with local mechanical forces, as indicated by their preferred distribution in high-tension areas, their responsiveness to tension-reduction therapy, and their high levels of mechanotransduction pathway signaling [14, 39]. Mechanotransduction is the process by which physical forces are converted into biochemical signals that are then integrated into cellular responses [40, 41]. In keloids, the mechanotransduction pathways may involve the transforming growth factor-β (TGF-β)/Smad, MAPK, integrin, RhoA/ROCK, Wnt/β-catenin, and TNF-α/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways [42]. Therefore, research into possible intersections between these mechanotransduction pathways and lipids is likely to identify pathways and potential molecules that could be targeted by anti-keloid therapeutic approaches.

Several lines of research indicated the potential interactions between lipids and mechanotransduction. Lipid rafts are specialized plasma membrane microdomains enriched in cholesterol and sphingolipids, which may serve as signaling compartments [43, 44]. As one type of lipid raft, caveolae are flask-shaped plasma membrane invaginations, whose major protein constituent is caveolin-1 [44]. Caveolae have already been proven to be important mechanotransduction sites in osteoblasts [45] and endothelial cells [46]. In endothelial cells, cholesterol depletion prevents the shear-induced activation of MAPKs [46] and caveolin-1 phosphorylation [47], and shear stress causes the phosphorylation of caveolin-1 and its recruitment to integrin sites [48]. Moreover, the β1 integrin-mediated mechanotransduction in endothelial cells is mediated by caveolae domains [47]. In osteoblasts, disruption of cholesterol-rich plasma membrane compartments significantly reduces hydrostatic pressure- and shear-induced mechanotransduction. Moreover, restoration of plasma membrane rafts causes osteoblasts to regain their mechanotranducing properties [45]. The relationship between lipid rafts/caveolae and mechanotransduction in keloids is just being recognized. Evidence for this is that KFs have markedly decreased caveolin-1 expression and that treatment of KFs with caveolin-1 cell-permeable peptide (cav-1p) inhibited the TGF-β1-induced up-regulation of collagen type I, fibronectin, and α-SMA mRNA and protein expression. Moreover, the inhibitory effect of cav-1p on KF fibronectin production could be blocked by inhibiting the ERK1/2, but not the p38 and JNK pathways [49]. Further research is needed to clarify the relationship between lipids and the active mechanotransduction in keloids.

Lipids and their metabolites may also interact and shape the mechanotransduction pathways in keloids. These lipid molecules could be potential targets for pharmaceutical intervention that aims to prevent or treat keloids. There is evidence that the lipid metabolite PGE2 can inhibit keloid formation as follows. First, in KFs, the IL-1β-induced up-regulation of COX-2 expression is impaired, resulting in a diminished stimulation of PGE2 secretion by IL-1β. Second, the treatment of KFs with PGE2 partially reverses the ability of TGF-β1 to up-regulate the production of collagen types I and III. Third, PGE2 inhibits KF cell migration and contraction. Thus, PGE2 has both anti-fibroplastic and anti-inflammatory effects on KFs [50]. Vitamin D may also be therapeutic for keloids, as shown by the fact that 1,25-dihydroxyvitamin D3 inhibits the TGF-β1-induced secretion by KFs of matrix proteins such as collagen I, fibronectin, and α-SMA [51]. Moreover, there is evidence that the TGF-β and vitamin D signaling pathways may converge on SMAD [52], or at least cross-talk via the binding of vitamin D receptor and Smad3 proteins to their cognate DNA recognition elements [53]. The alkylphospholipid analogue hexadecylphosphocholine (HePC) could also be useful as a therapy because it can inhibit the proliferation of KFs; notably, the enhanced reorganization of collagen I in KF that is induced by HePC relates to the up-regulation of the α2-integrin chain [54].


In summary, in keloids, lipids not only serve as indispensable skin components, they also actively participate in the chronic inflammation processes that drive the development and progression of keloids and are typically manifested at the edge of keloid skin. Supporting this is that the levels of the metabolic products of the AA and EPA cascades are changed in keloids relative to normal skin. It is also likely that there is an imbalance between the pro-inflammatory PGs and LTs and the anti-inflammatory LXs, PDs, and Rvs within these cascades that promotes inflammation. Lipids also serve as reservoirs of secondary messengers such as DAG and AA that contribute to fibroblast proliferation. Finally, there is evidence that mechanotransduction (an important etiological factor in keloid development) occurs in the lipid rafts and caveolae of the plasma membrane. Moreover, there are interactions between lipids and mechanotransduction pathway molecules, such as PGE2, Smads, and integrin. Thus, lipid molecules and their metabolic products may be potential pharmaceutical targets in interventions that aim to prevent, reduce, or even reverse keloid formation and/or progression.



Arachidonic acid


α-linolenic acid


Aspirin-triggered lipoxins






Dihomo-γ-linolenic acid


Docosahexaenoic acid


Extracellular matrix


Eicosapentaenoic acid


Eicosatrienoic acid


γ-linolenic acid




Hydroxyeicosapentaenoic acid


Hydroxyeicosatetraenoic acid


Hydroperoxyeicosapentaenoic acid


Hydroxyeicosatrienoic acid


Hydroperoxyeicosatetraenoic acid


Insulin-like growth factor






Linoleic acid




Lysophosphatidic acid






Mitogen-activated protein kinase


Nuclear factor kappa-light-chain-enhancer of activated B cells


Neuroprotectin D1


Phosphatidic acid


Protectin D








Protein kinase C


Phospholipase A2


Polyunsaturated fatty acid




Stearidonic acid


Transforming growth factor-β




  1. Lee JY, Yang CC, Chao SC, Wong TW: Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol. 2004, 26: 379-384.

    Article  PubMed  Google Scholar 

  2. Huang C, Akaishi S, Hyakusoku H, Ogawa R: Are keloid and hypertrophic scar different forms of the same disorder? A fibroproliferative skin disorder hypothesis based on keloid findings. Int Wound J. 2012, 10.1111/j.1742-481X.2012.01118.x. [Epub ahead of print],

    Google Scholar 

  3. Marneros AG, Norris JE, Watanabe S, Reichenberger E, Olsen BR: Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol. 2004, 122: 1126-1132.

    Article  CAS  PubMed  Google Scholar 

  4. Ogawa R: Keloid and hypertrophic scarring may result from a mechanoreceptor or mechanosensitive nociceptor disorder. Med Hypotheses. 2008, 71: 493-500.

    Article  PubMed  Google Scholar 

  5. Fong EP, Bay BH: Keloids - the sebum hypothesis revisited. Med Hypotheses. 2002, 58: 264-269.

    Article  CAS  PubMed  Google Scholar 

  6. Akaishi S, Ogawa R, Hyakusoku H: Keloid and hypertrophic scar: neurogenic inflammation hypotheses. Med Hypotheses. 2008, 71: 32-38.

    Article  CAS  PubMed  Google Scholar 

  7. Louw L, Engelbrecht AM, Cloete F, van der Westhuizen JP, Dumas L: Impairment in the fatty acid composition of keloids. Adv Exp Med Biol. 1997, 400B: 905-910.

    CAS  PubMed  Google Scholar 

  8. Louw L: Keloids in rural black South Africans. Part 1: general overview and essential fatty acid hypotheses for keloid formation and prevention. Prostaglandins Leukot Essent Fatty Acids. 2000, 63: 237-245.

    Article  CAS  PubMed  Google Scholar 

  9. Louw L, Dannhauser A: Keloids in rural black South Africans. Part 2: dietary fatty acid intake and total phospholipid fatty acid profile in the blood of keloid patients. Prostaglandins Leukot Essent Fatty Acids. 2000, 63: 247-253.

    Article  CAS  PubMed  Google Scholar 

  10. Louw L: Keloids in rural black South Africans. Part 3: a lipid model for the prevention and treatment of keloid formations. Prostaglandins Leukot Essent Fatty Acids. 2000, 63: 255-262.

    Article  CAS  PubMed  Google Scholar 

  11. Tachi M, Iwamori M: Mass spectrometric characterization of cholesterol esters and wax esters in epidermis of fetal, adult and keloidal human skin. Exp Dermatol. 2008, 17: 318-323.

    Article  CAS  PubMed  Google Scholar 

  12. Pochi PE: The pathogenesis and treatment of acne. Annu Rev Med. 1990, 41: 187-198.

    Article  CAS  PubMed  Google Scholar 

  13. Kao JS, Fluhr JW, Man MQ, Fowler AJ, Hachem JP, Crumrine D, Ahn SK, Brown BE, Elias PM, Feingold KR: Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol. 2003, 120: 456-464.

    Article  CAS  PubMed  Google Scholar 

  14. Ogawa R, Okai K, Tokumura F, Mori K, Ohmori Y, Huang C, Hyakusoku H, Akaishi S: The relationship between skin stretching/contraction and pathologic scarring: the important role of mechanical forces in keloid generation. Wound Repair Regen. 2012, 20: 149-157.

    Article  PubMed  Google Scholar 

  15. Miles EA, Allen E, Calder PC: In vitro effects of eicosanoids derived from different 20-carbon Fattyacids on production of monocyte-derived cytokines in human whole blood cultures. Cytokine. 2002, 20: 215-223.

    Article  CAS  PubMed  Google Scholar 

  16. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN: Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001, 2: 612-619.

    Article  CAS  PubMed  Google Scholar 

  17. Serhan CN, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B, Colgan SP, Stahl GL, Merched A, Petasis NA, Chan L, Van Dyke TE: Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol. 2003, 171: 6856-6865.

    Article  CAS  PubMed  Google Scholar 

  18. Yeh FL, Shen HD, Lin MW, Chang CY, Tai HY, Huang MH: Keloid-derived fibroblasts have a diminished capacity to produce prostaglandin E2. Burns. 2006, 32: 299-304.

    Article  PubMed  Google Scholar 

  19. Hayashi T, Nishihira J, Koyama Y, Sasaki S, Yamamoto Y: Decreased prostaglandin E2 production by inflammatory cytokine and lower expression of EP2 receptor result in increased collagen synthesis in keloid fibroblasts. J Invest Dermatol. 2006, 126: 990-997.

    Article  CAS  PubMed  Google Scholar 

  20. Sakaki H, Matsumiya T, Kusumi A, Imaizumi T, Satoh H, Yoshida H, Satoh K, Kimura H: Interleukin-1beta induces matrix metalloproteinase-1 expression in cultured human gingival fibroblasts: role of cyclooxygenase-2 and prostaglandin E2. Oral Dis. 2004, 10: 87-93.

    Article  CAS  PubMed  Google Scholar 

  21. Ueki S, Kato H, Kobayashi Y, Ito W, Adachi T, Nagase H, Ohta K, Kayaba H, Chihara J: Anti- and proinflammatory effects of 15-deoxy-delta-prostaglandin J2(15d-PGJ2) on human eosinophil functions. Int Arch Allergy Immunol. 2007, 143 (Suppl 1): 15-22.

    Article  CAS  PubMed  Google Scholar 

  22. Babcock TA, Novak T, Ong E, Jho DH, Helton WS, Espat NJ: Modulation of lipopolysaccharide-stimulated macrophage tumor necrosis factor-alpha production by omega-3 fatty acid is associated with differential cyclooxygenase-2 protein expression and is independent of interleukin-10. J Surg Res. 2002, 107: 135-139.

    CAS  PubMed  Google Scholar 

  23. De Caterina R, Cybulsky MI, Clinton SK, Gimbrone MA, Libby P: The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb. 1994, 14: 1829-1836.

    Article  CAS  PubMed  Google Scholar 

  24. Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y: Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol. 1997, 400B: 589-597.

    CAS  PubMed  Google Scholar 

  25. Datubo-Brown DD, Blight A: Inhibition of human fibroblast growth in vitro by a snake oil. Br J Plast Surg. 1990, 43: 183-186.

    Article  CAS  PubMed  Google Scholar 

  26. Kieran NE, Maderna P, Godson C: Lipoxins: potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Kidney Int. 2004, 65: 1145-1154.

    Article  CAS  PubMed  Google Scholar 

  27. Martins V, Valença SS, Farias-Filho FA, Molinaro R, Simões RL, Ferreira TP, e Silva PM, Hogaboam CM, Kunkel SL, Fierro IM, Canetti C, Benjamim CF: ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis. J Immunol. 2009, 182: 5374-5381.

    Article  CAS  PubMed  Google Scholar 

  28. Krönke G, Reich N, Scholtysek C, Akhmetshina A, Uderhardt S, Zerr P, Palumbo K, Lang V, Dees C, Distler O, Schett G, Distler JH: The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis. Ann Rheum Dis. 2012, 71: 1081-1087.

    Article  PubMed  Google Scholar 

  29. Börgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O’Sullivan TP, Guiry PJ, Goldschmeding R, Higgins DF, Godson C: Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J. 2011, 25: 2967-2979.

    Article  PubMed  Google Scholar 

  30. Serhan CN: Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2007, 25: 101-137.

    Article  CAS  PubMed  Google Scholar 

  31. Qu X, Zhang X, Yao J, Song J, Nikolic-Paterson DJ, Li J: Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J Pathol. 2012, 10.1002/path.4050. [Epub ahead of print],

    Google Scholar 

  32. Zhang G, Kazanietz MG, Blumberg PM, Hurley JH: Crystal structure of the cys2 activator-binding domain of protein kinase C delta in complex with phorbol ester. Cell. 1995, 81: 917-924.

    Article  CAS  PubMed  Google Scholar 

  33. Preiss J, Loomis CR, Bishop WR, Stein R, Niedel JE, Bell RM: Quantitative measurement of sn-1, 2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells. J Biol Chem. 1986, 261: 8597-8600.

    CAS  PubMed  Google Scholar 

  34. Tepper CG, Jayadev S, Liu B, Bielawska A, Wolff R, Yonehara S, Hannun YA, Seldin MF: Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity. Proc Natl Acad Sci U S A. 1995, 92: 8443-8447.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva MYu, Obeid LM, Hannun YA: Role for ceramide in cell cycle arrest. J Biol Chem. 1995, 270: 2047-2052.

    Article  CAS  PubMed  Google Scholar 

  36. Ishihara H, Yoshimoto H, Fujioka M, Murakami R, Hirano A, Fujii T, Ohtsuru A, Namba H, Yamashita S: Keloid fibroblasts resist ceramide-induced apoptosis by overexpression of insulin-like growth factor I receptor. J Invest Dermatol. 2000, 115: 1065-1071.

    Article  CAS  PubMed  Google Scholar 

  37. Lu F, Gao J, Ogawa R, Hyakusoku H, Ou C: Fas-mediated apoptotic signal transduction in keloid and hypertrophic scar. Plast Reconstr Surg. 2007, 119: 1714-1721.

    Article  CAS  PubMed  Google Scholar 

  38. Sellmayer A, Danesch U, Weber PC: Modulation of the expression of early genes by polyunsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids. 1997, 57: 353-357.

    Article  CAS  PubMed  Google Scholar 

  39. Ogawa R, Akaishi S, Huang C, Dohi T, Aoki M, Omori Y, Koike S, Kobe K, Akimoto M, Hyakusoku H: Clinical applications of basic research that shows reducing skin tension could prevent and treat abnormal scarring: the importance of fascial/subcutaneous tensile reduction sutures and flap surgery for keloid and hypertrophic scar reconstruction. J Nihon Med Sch. 2011, 78: 68-76. 10.1272/jnms.78.68.

    Article  Google Scholar 

  40. Huang H, Kamm RD, Lee RT: Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am J Physiol Cell Physiol. 2004, 287: C1-C11.

    Article  CAS  PubMed  Google Scholar 

  41. Ingber DE: Mechanobiology and diseases of mechanotransduction. Ann Med. 2003, 35: 564-577.

    Article  PubMed  Google Scholar 

  42. Huang C, Ogawa R: Fibroproliferative disorders and their mechanobiology. Connect Tissue Res. 2012, 53: 187-196.

    Article  CAS  PubMed  Google Scholar 

  43. Simons K, Toomre D: Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000, 1: 31-39.

    Article  CAS  PubMed  Google Scholar 

  44. Allen JA, Halverson-Tamboli RA, Rasenick MM: Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci. 2007, 8: 128-140.

    Article  CAS  PubMed  Google Scholar 

  45. Ferraro JT, Daneshmand M, Bizios R, Rizzo V: Depletion of plasma membrane cholesterol dampens hydrostatic pressure and shear stress-induced mechanotransduction pathways in osteoblast cultures. Am J Physiol Cell Physiol. 2004, 286: C831-C839.

    Article  CAS  PubMed  Google Scholar 

  46. Park H, Go YM, St John PL, Maland MC, Lisanti MP, Abrahamson DR, Jo H: Plasma membrane cholesterol is a key molecule in shear stress-dependent activation of extracellular signal-regulated kinase. J Biol Chem. 1998, 273: 32304-32311.

    Article  CAS  PubMed  Google Scholar 

  47. Radel C, Carlile-Klusacek M, Rizzo V: Participation of caveolae in beta1 integrin-mediated mechanotransduction. Biochem Biophys Res Commun. 2007, 358: 626-631.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Radel C, Rizzo V: Integrin mechanotransduction stimulates caveolin-1 phosphorylation and recruitment of Csk to mediate actin reorganization. Am J Physiol Heart Circ Physiol. 2005, 288: H936-H945.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang GY, Yu Q, Cheng T, Liao T, Nie CL, Wang AY, Zheng X, Xie XG, Albers AE, Gao WY: Role of caveolin-1 in the pathogenesis of tissue fibrosis by keloid-derived fibroblasts in vitro. Br J Dermatol. 2011, 164: 623-627.

    Article  CAS  PubMed  Google Scholar 

  50. Sandulache VC, Parekh A, Li-Korotky H, Dohar JE, Hebda PA: Prostaglandin E2 inhibition of keloid fibroblast migration, contraction, and transforming growth factor (TGF)-beta1-induced collagen synthesis. Wound Repair Regen. 2007, 15: 122-133.

    Article  PubMed  Google Scholar 

  51. Zhang GY, Cheng T, Luan Q, Liao T, Nie CL, Zheng X, Xie XG, Gao WY: Vitamin D: a novel therapeutic approach for keloid, an in vitro analysis. Br J Dermatol. 2011, 164: 729-737.

    Article  CAS  PubMed  Google Scholar 

  52. Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, Kashiwagi K, Toriyabe T, Kawabata M, Miyazono K, Kato S: Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators. Science. 1999, 283: 1317-1321.

    Article  CAS  PubMed  Google Scholar 

  53. Subramaniam N, Leong GM, Cock TA, Flanagan JL, Fong C, Eisman JA, Kouzmenko AP: Cross-talk between 1, 25-dihydroxyvitamin D3 and transforming growth factor-beta signaling requires binding of VDR and Smad3 proteins to their cognate DNA recognition elements. J Biol Chem. 2001, 276: 15741-15746.

    Article  CAS  PubMed  Google Scholar 

  54. Blume-Peytavi U, Geilen CC, Sommer C, Almond-Roesler B, Orfanos CE: The phospholipid analogue hexadecylphosphocholine (HePC) inhibits proliferation of keloid fibroblasts in vitro and modulates their fibronectin and integrin synthesis. Arch Dermatol Res. 1997, 289: 164-169.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Rei Ogawa.

Additional information

Competing interests

The authors declare that they have no competing interests. There are no non-financial competing interests.

Authors’ contributions

All authors have made substantial contributions to this work. CH designed and drafted the manuscript after a literature research. RO guided the literature research and the drafting of the manuscript, and made the final corrections to the manuscript. Both authors have read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Huang, C., Ogawa, R. Roles of lipid metabolism in keloid development. Lipids Health Dis 12, 60 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: