Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1

Abstract

Lipid droplets (LDs) provide a reservoir for triacylglycerol storage and are a central hub for fatty acid trafficking and signaling in cells. Lipolysis promotes mitochondrial biogenesis and oxidative metabolism via a SIRT1/PGC-1a/PPARa-dependent pathway through an unknown mechanism. Herein, we identify that monounsaturated fatty acids (MUFAs) allosterically activate SIRT1 toward select peptide-substrates such as PGC-1a. MUFAs enhance PGC-1a/ PPARa signaling and promote oxidative metabolism in cells and animal models in a SIRT1-dependent manner. Moreover, we characterize the LD protein perilipin 5 (PLIN5), which is known to enhance mitochondrial biogenesis and function, to be a fattyacid-binding protein that preferentially binds LDderived monounsaturated fatty acids and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Thus, these studies identify the first-known endogenous allosteric modulators of SIRT1 and characterize a LD-nuclear signaling axis that underlies the known metabolic benefits of MUFAs and PLIN5.

Monounsaturated Fatty Acids in Obesity-Related Inflammation

“…Oleate is also a direct PPARα agonist [ 150 ]. These mechanisms inhibit NF-κB activity ( Figure 3 ) [ 151 , 152 ], explaining, at least in part, the resorption of hepatic inflammation by MUFAs.…”

Resveratrol‐induced remodelling of myocellular lipid stores: A study in metabolically compromised humans

“…In highly insulin‐sensitive trained athletes, IMCL is stored predominantly in type I muscle fibres and dispersed alongside myofibrils (intermyofibrillar (IMF) LDs) in numerous small LDs (Daemen et al, 2018), with significantly more PLIN5 present in athletes than in T2DM individuals, a LD phenotype we referred to as an ‘athlete like phenotype’ (Gemmink et al, 2020). PLIN5 is a LD coat protein known to promote mitochondrial biogenesis and function (Bosma et al, 2013), in a SIRT1 and PGC1α‐dependent fashion (Najt et al, 2020). Upon exercise training, the morphological LD characteristics in patients with T2DM changed towards an athlete‐like phenotype, along with improved insulin sensitivity (Daemen et al, 2018).…”

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

“…While we cannot exclude the possibility of dominant negative effects due to an inactive truncation product, limited experiments with heterozygous animals (not shown) did not reproduce any phenotypes observed in homozygous knockouts. The lipid droplet protein perilipin-5, which signals via Sirt1/PPAR-α to drive mitochondrial biogenesis and fat oxidation ( Najt et al, 2020 ), was 25% lower in Alkbh7 -/- vs. WT. In addition, fructose-1,6-bisphosphatase 2 (FBP2/PFK2) was 31% lower in Alkbh7 -/- vs. WT, a finding typically associated with acceleration of glycolysis ( Li et al, 2013 ).…”

“…2A) revealing several differences which may underlie the metabolic phenotype of the knockout animals. A The lipid droplet protein perilipin-5, which signals via Sirt1/PPAR-α to drive mitochondrial biogenesis and fat oxidation, 22 was 25% lower in Alkbh7 -/vs. WT.…”