Identification pathways of enzymes involved in biosynthesis of a novel class of anti-diabetic lipids

We recently identified a novel class of mammalian lipids which have anti-diabetic and anti-inflammatory effects. These lipids are branched Fatty-Acid-esters-of-Hydroxy-Fatty-Acids (FAHFAs). A member of this class, Palmitic-Acid-Hydroxy-Stearic-Acid (PAHSA) is present in serum and many mouse and human tissues. PAHSA levels in adipose tissue (AT) are regulated by Carbohydrate-response element binding protein (ChREBP). PAHSA levels are reduced in serum and tissues of obese, insulin-resistant versus lean insulin-sensitive mice. In insulin-resistant versus insulin-sensitive people, PAHSA levels in serum and AT are reduced and levels correlate highly with insulin-sensitivity. In insulin-resistant mice, PAHSA administration lowers blood glucose, stimulates GLP-1 and insulin secretion, and improves glucose-tolerance and insulin-sensitivity. In vitro, PAHSAs augment insulin-stimulated glucose transport in adipocytes through the G-protein coupled receptor, GPR120 and also potentiate glucose-stimulated insulin secretion. PAHSAs could potentially be administered as drugs, or the pathways that regulate them in vivo perturbed to increase their levels for therapeutic effects.

This proposal’s objective is to identify the pathways and biosynthetic enzymes that control PAHSA levels/biosynthesis. This will improve our understanding of their biology, the mechanisms by which PAHSA levels are reduced in insulin-resistant states and their therapeutic potential to treat Type 2 diabetes (T2D). These objectives are in alignment with BADERC’s mission to cure of T2D and associated complications.
Aim #1: Investigate ChREBP’s role in controlling PAHSA levels and biosynthetic activity.
Aim #2: Identify pathways/enzymes involved in PAHSA biosynthesis. To achieve these aims, we’ll take a systematic genetic approach in combination with a biosynthetic activity assay developed by our lab.