Melanin, a dark pigment in our skin, eyes, and hair, is produced by melanosomes, specialised subunits in melanocyte cells. Melanocytes are activated when exposed to UV radiation. They respond by producing melanin to protect our cells from harmful UV radiations and then return to a resting state, to prepare themselves for another round of activation.
What are the key metabolic cues for melanocyte activation, pigment production and recovery?
Rajesh Gokhale from the National Institute of Immunology collaborated with Vivek Nararajan at the Institute of Genomics and Integrative Biology and other labs in India and abroad to tackle the problem.
They harvested mouse melanoma cells during the preparatory, pigmented, and recovery phases. and did a genome-wide transcriptome analysis. They found that the fatty acid synthesis pathway was upregulated in the pigmented phase.
How does fatty acid synthesis increase during pigmentation?
The team examined the transcription factors involved in fatty acid biosynthesis. A prominent transcription factor that emerges during the melanogenic phase is the sterol regulatory element-binding transcription factor 1, Srebf1. It is this protein that regulates lipid metabolism, ensuring efficient fatty acid synthesis by activating its target gene, a fatty acid synthase.
The researchers used an inhibitor of the transcription factor, 25-hydroxycholesterol, to investigate its role in pigmentation. The pigmentation decreased, confirming the transcription factor as a potential target for regulating melanogenesis.
The decrease also suggested that fatty acid synthesis is important during pigmentation.
So can pharmacologically targeting fatty acid metabolism reduce hyper-pigmentation?
The researchers used a guinea pig model to find out. They divided guinea pig skin into sections. One section was exposed to only UV, and, on another section exposed to UV, they applied orlistat, an FDA-approved fatty acid synthase inhibitor.
Orlistat molecule, ball and stick model. Image: Vaccinationist via Wikimedia Commons
Enhanced induction of pigment was seen in the skin section exposed to UV. The orlistat-treated, UV-exposed, skin section showed reduced pigmentation.
Though orlistat is approved for oral intake to manage obesity, the findings suggest that repurposing it for topical application may help resolve hyperpigmentation as well.
Further detailed screening of fatty acid synthesis inhibitors could provide a new class of pigmentation modulators for skin pigmentation disorders, say the scientists.
PLOS Biology 20 (5): e3001634 (2022);
DOI: 10.1371/journal.pbio.3001634
Reported by Tanya Jain
National Institute of Immunology, New Delhi
STEAMindiaReports 
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