Treatment for LPP like conditions: lipids and diabetes drugs?
From: Europe PMC
If the PPAR-γ receptor is not functioning properly, it might be downregulated, leading to an inability to metabolize harmful lipids effectively. To address this, we can use a type of drug called an agonist. Unlike antagonists, which block receptor activity, agonists stimulate receptors, effectively “upregulating” them to improve their function. This is particularly relevant when exploring treatments for Lichen Planopilaris (LPP), a form of primary cicatricial alopecia.
Returning to the study titled “PPAR-γ Agonists and Their Role in Primary Cicatricial Alopecia” by Sarawin Harnchoowong and Poonkiat Suchonwanit, published in PPAR Research in 2017, the authors explore the therapeutic potential of PPAR-γ agonists, specifically pioglitazone, in treating LPP. Pioglitazone is well-known for its use in managing diabetes mellitus due to its ability to increase insulin sensitivity. However, it also possesses anti-inflammatory properties, making it a candidate for treating inflammatory conditions like LPP.
Keep in mind, pioglitazone and other PPAR-γ receptor agonists are primarily diabetes drugs that are used to improve insulin sensitivity and regulate blood sugar levels in patients with type 2 diabetes. They are usually prescribed when patients have not adequately responded to other diabetes medications such as metformin or sulfonylureas. These drugs help by activating the PPAR-γ receptor, which plays a crucial role in glucose metabolism and fat storage, ultimately enhancing the body’s response to insulin. Could topical metformin or sulfonylureas also be used as well? What about other diabetes drugs? Could they be explored in dermatology for lipid production?
The authors discuss several case reports and clinical trials that highlight the efficacy of pioglitazone in managing LPP.
- Mirmirani and Karnik, 2009: This case report involved a single patient with LPP treated with oral pioglitazone hydrochloride at a dose of 15 mg/day for 14 months. The patient showed clinical improvement within two months, a marked decrease in inflammation after six months, and remained symptom-free for a year. Lichen planopilaris treated with a peroxisome proliferator-activated receptor gamma agonist - PubMed
- Baibergenova and Walsh, 2012: This case series included 21 patients with LPP, two patients with fibrosing alopecia in a pattern distribution (FAPD), and one patient with frontal fibrosing alopecia (FFA). The patients received oral pioglitazone hydrochloride at a starting dose of 15 mg/day, which could be increased to 30 mg/day if there were no adverse drug reactions. Five patients achieved remission, 12 showed improvement, three had no improvement, and four experienced adverse reactions leading to withdrawal from the study. Use of pioglitazone in patients with lichen planopilaris - PubMed
- Spring et al., 2013: This study involved 22 patients with LPP treated with oral pioglitazone hydrochloride at 15 mg/day for one year. Three patients showed remission with no relapse, five had improvement with lower disease activity, four experienced improvement but had relapses, and ten had negative results. Lichen planopilaris treated by the peroxisome proliferator activated receptor-γ agonist pioglitazone: lack of lasting improvement or cure in the majority of patients - PubMed
- Mesinkovska et al., 2015: This retrospective case series included 18 patients with LPP and four patients with FFA. Patients received oral pioglitazone hydrochloride at a dose of 15 mg/day for a median of 10.5 months. Sixteen patients showed marked improvement, five had stable disease, one had disease progression, and adverse reactions included lower extremities edema, weight gain, dizziness, resistant hypertension, and mild transaminitis. The use of oral pioglitazone in the treatment of lichen planopilaris - PubMed
So, it seems that PPAR-γ drugs are important for scarring alopecias. But what I also noticed in the literature are case reports of topical metformin being used to treat Central Centrifugal Cicatricial Alopecia (CCCA).
One study, “Topical Metformin for the Treatment of Central Centrifugal Cicatricial Alopecia” by Erinolaoluwa F. Araoye, Jamael A. L. Thomas, and Crystal U. Aguh, published in JAAD Case Reports in 2020, presents two cases of hair regrowth after the use of topical metformin for CCCA. The study highlights that CCCA is a progressive scarring alopecia predominately occurring in women of African descent. Metformin, commonly used for glycemic control in type 2 diabetes, has shown efficacy in improving fibrosis in fibroproliferative disorders through the activation of adenosine monophosphate-activated protein kinase (AMPK). The patients in this study experienced substantial hair regrowth after the topical application of 10% metformin cream over several months.
So, why are these type 2 diabetes drugs having some success in scarring alopecias?
Both PPAR-γ receptor agonists and metformin have significant anti-inflammatory effects. Chronic inflammation is a key factor in the pathogenesis of scarring alopecias like LPP and CCCA. Therefore, any drug effective at reducing inflammation may help prevent further follicular damage and scarring.
However, this might be a secondary benefit. The primary issue seems to be dysfunction of the sebaceous glands and the various sebocytes. The inability of their PPAR-γ receptors causes toxic lipids to build up. PPAR-γ agonists play a crucial role in lipid metabolism and homeostasis.
In scarring alopecias, disrupted lipid metabolism can contribute to the pathological process. By improving lipid metabolism, PPAR-γ agonists may help restore the normal function of sebaceous glands and hair follicles by reactivating PPAR-γ receptor activity, thus increasing the metabolism of local lipids and essentially “cleaning” the toxic lipids, reducing the inflammatory response, and preventing scarring.
On the other hand, metformin helps with lipid metabolism primarily through its activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK activation by metformin inhibits the synthesis of fatty acids and cholesterol by downregulating the expression of enzymes involved in lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). This reduces the accumulation of lipids in cells.
Metformin also promotes the oxidation of fatty acids by enhancing the activity of carnitine palmitoyltransferase 1 (CPT1), an enzyme critical for the transport of fatty acids into mitochondria where they are oxidized to produce energy. This process helps reduce lipid levels in tissues.
So, I think the interplay between the two is this: PPAR-γ agonists help the cells in the sebaceous glands and hair follicles metabolize lipids, clearing the toxic buildup of lipids in the tissue. Metformin, meanwhile, reduces overall lipid production, which can help attenuate the amount of toxic lipids.
PPAR-GAMMA RECEPTORS AND RETINOID RECEPTORS.
The study titled “Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA” by Vikas Chandra, Pengxiang Huang, et al., provides a comprehensive analysis of how Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) and Retinoid X Receptor Alpha (RXR-α), two nuclear receptors, interact with each other and DNA to regulate gene expression. This research is particularly noteworthy as it reveals, for the first time, the structure of these receptors in their fully intact form, rather than as isolated parts.
The authors explain that PPAR-γ and RXR-α form a non-symmetric complex, where the ligand-binding domain (LBD) of PPAR-γ interacts with multiple domains in both proteins, thereby enhancing their ability to bind to DNA. This interaction is crucial for regulating the expression of genes involved in important processes like metabolism and inflammation.
To explain this in simpler terms, PPAR-γ and RXR-α function together like a specialized team of switches. PPAR-γ acts as a switch that can be activated by specific molecules known as ligands—these ligands are like keys that fit into a lock. When PPAR-γ is activated by a ligand, it pairs up with RXR-α, another switch that is already prepared to assist. This partnership allows the complex to bind to specific regions of DNA, much like a key fitting into a lock to open a door.
For instance, in sebocytes—cells that produce sebum, the oily substance in the skin—this binding can either activate or deactivate the production of certain proteins by influencing how the DNA is interpreted, similar to how adjusting settings on a machine can change its output. This collaboration between PPAR-γ and RXR-α is essential for controlling various cellular processes, including those related to skin health and metabolic functions. In this case, we are interested in how cells regulate their lipid metabolism as well as possible genetic defects that could make conditions like Androgenetic alopecia and Lichen Planopilaris worse.
PPAR-GAMMA and Retinoids (Low Dose Oral Isotretinoin, Topical Adapalene and Topical Tretinoin)
I believe it would be valuable for researchers to investigate the potential of combining a PPAR-GAMMA agonist with a retinoid as a treatment for conditions like Lichen Planopilaris. This idea is supported by the fact that the PPAR-GAMMA receptor works in tandem with the Retinoid X Receptor (RXR-α), as demonstrated in the study by Vikas Chandra, Pengxiang Huang, et al. The study reveals how these receptors form a complex that regulates gene expression, particularly in metabolic and inflammatory pathways.
Given that Lichen Planopilaris and similar autoimmune scarring alopecias are thought to involve dysfunctions in PPAR-GAMMA receptors, it stands to reason that there could also be issues with retinoid receptors. Since these receptors are so closely linked in their function, addressing both could potentially lead to more effective treatments.
Combining a PPAR-GAMMA agonist, like pioglitazone, with a retinoid, such as a low dose of oral isotretinoin or topical tretinoin, could enhance the therapeutic effects, targeting the underlying dysfunction more comprehensively.