ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids

Abstract

Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals1,2. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic1,3. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum1. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases1,4–7. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80–90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.

Lipidomic alterations in the cerebral cortex and white matter in sporadic Alzheimer’s disease

“…FAHFA, derived from the activity of patatin-like phospholipase domain containing 2 (PNPLA2, also known ATGL) (Patel et al, 2022) are involved in glucose homeostasis, insulin resistance and anti-inflammatory functions. FAHFA are also linked to the nuclear factor erythroid 2-related factor 2 (Nrf2), which participates in antioxidant cell defenses (Kuda et al, 2018; Wood, 2020).…”

Adipose triglyceride lipase is regulated by CAMKK2-AMPK signaling and drives advanced prostate cancer

“…However, these additional enzymatic activities have been poorly studied. ATGL has also been described to play a role in autophagy/lipophagy 70 . Given the previous reports on the role of autophagy in CRPC 20 , it would be of interest to test if ATGL plays a role in this process, and if the S404A mutant interferes with this function.…”

PNPLA1-Mediated Acylceramide Biosynthesis and Autosomal Recessive Congenital Ichthyosis

“…In addition, the epidermal levels of (O-acyl)-ω-hydroxy fatty acid (OAHFA) species, particularly (O-linoleoyl)-o-hydroxy FA (OLHFA), were markedly decreased with a reciprocal increase in corresponding ω-hydroxy ULCFAs in Pnpla1 −/− mice [ 7 , 24 ]. Interestingly, the most recent findings demonstrate that adipose triglyceride lipase, namely PNPLA2, acts as a transacylase in mammals to catalyze the formation of ester bonds in fatty acid esters of hydroxy fatty acids (FAHFAs) [ 25 ]. These results suggest that PNPLA1 may also be involved in the linoleoyl ω-O-esterification of free ω-hydroxy ULCFAs, although OAHFAs may be generated indirectly after the degradation of acylceramides.…”