An antisteatosis response regulated by oleic acid through lipid droplet–mediated ERAD enhancement

Abstract

Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here, we show that OA benefits Caenorhabditis elegans by activating the endoplasmic reticulum (ER)–resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet–dependent enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal an unexpected mechanism of FA signal transduction, as well as a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate some benefits of the OA-rich Mediterranean diet.

Early life changes in histone landscape protect against age-associated amyloid toxicities through HSF-1 dependent regulation of lipid metabolism

“…Recent studies revealed that exogenous addition of the FAT-7 product oleic acid to the growth media extends worm lifespan and protects against amyloid-induced proteotoxicity 25,42,43 . Indeed, comparison between the onset of paralysis in Q40::YFP worms grown on ash-2 RNAi bacteria or on media supplemented with oleic acid revealed a striking resemblance, with both interventions causing a comparable delay in the onset of paralysis resemblance (Fig.…”

“…Changes in lipid composition and metabolism are increasingly being associated with extended lifespan and healthspan in a variety of different organisms 25,42,43,[59][60][61] . For instance, an increase in membrane-associated MUFAs over PUFAs has been shown to associate with longer lifespan, possibly due to the reduced peroxidation sensitivity of MUFAs and hence a mitigation of ageassociated oxidative damage 62 .…”

“…Similarly, in a variety of different longevity paradigms, including insulin signaling mutants, both synthesis, mobilization and subsequent utilization of neutral acids like oleic acid was found to be significantly increased 44 . Moreover, supplementation with oleic acid supplementation has been shown to be beneficial for extended lifespan and healthspan 25,42,43 .…”