Barrier Lipid Production

You know by now that the significant part of the moisture barrier is the barrier lipids (Ceramides, Cholesterol and Fatty Acids). In a normal state, the skin produces fatty acids from the basal layer to the Stratum Granulosum. This increase in fatty acid content in the cell layers activates PPARs, as fatty acids are one of the most common PPAR agonists. PPAR activation leads to the enhancement of Cholesterol and Ceramide production. (2) It is a feed-forward system where the resulting Fatty acid, Ceramide and Cholesterol can activate further PPAR resulting in an abundance of these Barrier lipids in the Stratum Granulosum. In essence, PPAR here acts as an orchestrator to ensure enough of each barrier lipid in the skin for lamellar body production.

Adapted from: Feingold, K. R. (2007). Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis. Journal of Lipid Research, 48(12), 2531–2546.

Lamellar Body Formation and Secretion

For barrier lipids to be secreted, they must first be packed into sacs called lamellar bodies. Fatty acids serve two purposes here: 1) serve as a building block for Ceramides and 2) convert them into Phospholipids to be packed into lamellar bodies. On the other hand, Ceramides need to be converted into Glucosylceramide (the more water-soluble ceramide) and Sphingomyelin. Finally, Cholesterol is just packaged up as Cholesterol in lamellar bodies.

The role of PPAR here is during the transport and packaging of lamellar bodies. PPAR seems to initiate the lamellar body formation through the action of ATP-Binding Cassette Transporter family: ABCG1 and ABCA12. ABCG1 forms the lamellar membrane and recruits the lamellar lipids to be packaged (3), while ABCA12 transports Glucosylceramide into the lamellar bodies. (4) Once the lamellar bodies are formed, the increase in PPAR expression due to barrier lipid formation causes the secretion of lamellar bodies in the Stratum Granulosum (SG)-Stratum Corneum(SC) interface. (5)

Processing of Precursor Lipids

Once the lamellar bodies are secreted in the SG-SC interface, these barrier lipids are not yet fully processed. For them to properly merge with the existing lamellar layer, the Glucosylceramides and Sphingomyelin need to be processed into Ceramides, and the Phospholipids need to be converted into Fatty acids. Incidentally, the processing enzymes (inactive form) have also been packed in the lamellar bodies. Once they reach the SC, these processing enzymes activate and start the conversion of the precursor lipids. One enzyme in particular (B-glucocerebrosidase) is essential in forming functional ceramides. It is active around a pH of 5, and its activity is increased by PPAR activation. (6)

Corneocyte Maturation

Aside from the barrier lipids, the other major moisture barrier component is the corneocyte (aka the bricks). As the Keratinocytes differentiate, their membrane gets bolstered with a rigid envelope composed of Involucrin, Loricrin and other proteins. This cornified envelope becomes more compact and makes the corneocyte more resistant to chemical and mechanical damage. In addition, the enzyme Transglutaminase-1 attaches certain Ceramides to the cell, coating the cell in a lipid envelope. This lipid envelope serves as an attachment point for lamellar layers.

PPAR’s role here is to push forward cell differentiation. It is interesting to note that PPAR appears to be the main orchestrating body coordinating barrier lipid formation, lamellar body secretion and cornification in cell differentiation.

Antimicrobial Peptides

In addition to the barrier lipids and processing enzymes in lamellar bodies, some short-peptides called Antimicrobial Peptides (AMPs) are included. These peptides are one of the ways that the skin fights off microbes, as they are effective against various Bacteria, Fungi and Viruses. (Side note: In Rosacea, there is a decrease in AMPs in the skin, which leads to easier colonization by harmful bacteria or fungi). One particular AMP is β-Defensin. PPAR activation also significantly increases βD2 and βD3 in the skin contributing to the protective function of the newly formed barrier. (7)

Wound Healing

PPAR’s function in wound healing is quite interesting. When a wound is present in the skin, there are multiple inflammatory responses within the wound. One of these inflammatory responses is TNFa-induced apoptosis which essentially kills all the affected cells in the wound. PPAR expression was seen to be increased in the wound edge in non-affected cells. Its function is to confer resistance to apoptotic signals in the wound edge, creating a barrier around the wound. Once the inflammation is toned down, these barrier cells migrate and undergo differentiation. PPAR essentially organizes gene expression around the wound, leading to survival, migration and differentiation of keratinocytes. (8)

Anti-Inflammation

Inflammation is a very complex process that has a lot of triggers. Once started, it forms a cascade of pro-inflammatory molecules and pathways that activates multiple inflammatory pathways. However, as soon as the inflammation starts, the skin produces anti-inflammatory molecules. The visible inflammation in the skin results from the balance between pro-inflammatory and anti-inflammatory systems.
Most of the pro-inflammatory genes are under the control of the AP-1 and NF-kB signaling pathways. Most skin damages pass through either or both of these signaling pathways. Interestingly, PPAR was shown to tone down both NF-kB and AP-1 signaling inside the nucleus. (9) PPARa can inhibit NF-kB in multiple steps, but its action is mainly to prevent the degradation of IkBa, which is an inhibitor for NF-kB. IkBa binds to inactive NF-kB, so if there are more IkBa in the nucleus, NF-kB remains bound and won't be able to activate target genes. On the other hand, PPAR directly inhibits AP-1 signaling through the binding of c-Jun. Hence AP-1 is also toned down when PPAR is activated. PPAR also acts on two minor inflammatory signaling pathway: NFAT and STAT.

Adapted from: Delerive, P., Fruchart, J. C., & Staels, B. (2001). Peroxisome proliferator-activated receptors in inflammation control. The Journal of endocrinology, 169(3), 453–459. https://doi.org/10.1677/joe.0.1690453

What are the benefits of the topical application of PPAR agonists?

Barrier Function

Topical treatment with PPARa, PPARb/d activators increased Cholesterol, fatty acids, and sphingolipid synthesis in the epidermis. There was also an increase in the activity of Serine Palmitoyltransferase, Ceramide Synthase, and HMG-CoA synthase in human organotypic cultures with PPARa activator. On the other hand, PPARg did not exert significant effects on epidermal lipid synthesis. (10) In addition, topical treatment of adult mice with PPARa activators (Clofibrate and Farnesol) decreased epidermal thickness, while the expression of structural proteins. Although PPARa activation leads to no change in TEWL under basal conditions, it accelerated permeability barrier repair following abrogation by either tape stripping or 10% SDS treatment. (11) It is crucial to note that PPARs work on accelerating barrier repair when you have a damaged barrier. If your skin is not damaged, they don't change your basal TEWL.

Source: Elias, P. (2022). Optimizing emollient therapy for skin barrier repair in atopic dermatitis. Annals Of Allergy, Asthma &Amp; Immunology, 128(5), 505-511. https://doi.org/10.1016/j.anai.2022.01.012

Anti-inflammation

Most of the work regarding anti-inflammation is through novel PPAR compounds targeted toward inflammatory diseases. Examples of these are GED-0507-34L (PPARg agonist), GW7647 (PPARa), and Wy-14643 (PPARa). There are some PPARg ligand studies, but the anti-inflammatory effect is mainly through PPARa. Natural ligands like Palmitoylethanolamide were also studied for their anti-inflammatory role through PPAR. See the table below for Studies and Clinical Trials.

Retinoid-Induced Irritation

This benefit is an exciting one. We know that Retinoids can cause dryness, barrier damage, irritation and even dermatitis. The exact mechanism isn't fully known, but some authors theorize that it has something to do with the dimerization of nuclear hormone receptors in the nucleus. For Retinoic acid to work, it has to bind RARs, which heterodimerize with RXRs. The number of RXRs in the nucleus is under tight control, and PPARs can bind RAR and RXR. (12) One interesting theory is that the side effects are due to RAR-RXR heterodimers that are not DNA-bound. PPAR may bind to RXR and reduce the non-DNA-bound RAR-RXR through direct competition.
In addition, PPAR's primary function is promoting barrier homeostasis and controlling inflammation. It could also just simply counteract the temporary barrier-damaging effects of retinol. In an interesting study, PPARa agonists WY-14643 and LXR agonist 22-Hydroxycholesterol were able to blunt the increase in TEWL caused by Retinoic acid. In addition, Retinoic acid treatment caused hyperproliferation and treatment with PPARa agonist reduced the proliferation. PPAR agonists also reduced retinoid-induced IL-1a, TNF-a and IL-8 mRNA expression (important mediators of retinoid dermatitis). (13) Another study showed that combining retinoic acid with a PPARa agonist increased the collagen content in the skin significantly: RA with 47%, 70% with 10-HSA, and 240% with a combination of both.

Studies and Clinical Trials

References:

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