<i>Caenorhabditis elegans</i> utilizes dauer pheromone biosynthesis to dispose of toxic peroxisomal fatty acids for cellular homoeostasis

146

180

Dietary fat accumulates in lipid droplets or endolysosomal compartments that undergo selective expansion under normal or pathophysiological conditions. We find that genetic defects in a peroxisomal β-oxidation pathway cause size expansion in lipid droplets that are distinct from the lysosome-related organelles in Caenorhabditis elegans. Expansion of lipid droplets is accompanied by an increase in triglycerides (TAG) that are resistant to fasting-or TAG lipase-triggered lipolysis. Nevertheless, in mutant animals, a diet poor in vaccenic acid reduced the TAG level and lipid droplet size. Our results implicate peroxisomal dysfunction in pathologic lipid droplet expansion in animals and illustrate how dietary factors modulate the phenotype of such genetic defects.peroxisome | β-oxidation | daf-22 | dhs-28 | maoc-1

Section: Discussioncontrasting

confidence: 47%

Genetic and dietary regulation of lipid droplet expansion in Caenorhabditis elegans

Zhang

Box

et al. 2010

146

180

“…At 3 d of age, >95% of WT animals were at the young adult stage (25). When atx-2 was down-regulated in eat-2(ad1116) animals after hatching, by day 3 nearly all atx-2(RNAi)-treated animals were young adults, similar to the developmental pace in WT animals.…”

Section: Resultsmentioning

confidence: 73%

Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

Bar

Charar

Dorfman

et al. 2016

Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.Caenorhabditis elegans | metabolism | mTOR pathway | TORC1 D ietary restriction (DR), limiting food consumption below ad libitum to levels that do not cause malnutrition, is a highly conserved metabolic intervention. Different DR regimes extend the lifespan of most tested animal species (1). Moreover, DR regimens have been found to reduce the risk of diabetes in monkeys and to positively change metabolic health biomarkers in humans (2). Lifelong DR causes reduced body size, lower fat levels, and a smaller brood size (3-6). Although the pathways by which DR extends lifespan have been thoroughly investigated, less is known about the causes of reduced body size and fat content.Multiple DR regimens have been developed for Caenorhabditis elegans (7). Surprisingly, the different DR regimens vary in the genes essential for lifespan extension (7). For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate. Unlike bacterial dilution, this model was shown to be independent of both daf-16 and aak-2, at least with respect to lifespan (7).The mechanistic target of rapamycin (mTOR) pathway is a key regulator of multiple processes, including transcription and translation, protein and lipid synthesis, cell growth and size, and cellular metabolism (9). It contains two main protein complexes, mTOR complex 1 (TORC1) and complex 2 (TORC2) (10). TOR...

“…Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig. 1C) (11,(17)(18)(19). These enzymes are homologous to mammalian peroxisomal enzymes that process very long chain fatty acids, branched-chain fatty acids, and bile acid intermediates (20).…”

mentioning

confidence: 99%

“…Biosynthesis of the side chains of the ascarosides requires peroxisomal β-oxidation cycles that shorten the side chains by two carbons per cycle (11,(17)(18)(19). Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig.…”

mentioning

confidence: 99%

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

158

Caenorhabditis elegans uses ascaroside pheromones to induce development of the stress-resistant dauer larval stage and to coordinate various behaviors. Peroxisomal β-oxidation cycles are required for the biosynthesis of the fatty acid-derived side chains of the ascarosides. Here we show that three acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo-and heterodimers with distinct substrate preferences. Mutations in the acyl-CoA oxidase genes acox-1, -2, and -3 led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo-and heterodimers displayed different sidechain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify environmental conditions, including high temperature and low food availability, that induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, our work uncovers an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under specific environmental conditions. dauer | pheromone | ascaroside | beta-oxidation | acyl-CoA oxidase