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Lysosomal targetomics in ghrKO mice reveals a role for chaperone-mediated autophagy in shaping the nucleocytosolic acetyl-coA production pathway

ABSTRACT: Mice deficient for growth hormone receptor (ghrKO) have a dramatic lifespan extension, through an unknown mechanism. Compared to normal littermates,ghrKO mice have elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in ghrKO mice specifically downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Using a combination of cell culture and mouse models, we show that CMA is both necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Degradation of ACLY and ACSS2 by CMA prevents aberrant accumulation of lipid droplets in NIH3T3 cells. Nucleocytosolic acetyl-coA has been implicated in longevity. Elevated CMA in ghrKO mice might contribute to their long lifespan by diminishing nucleocytoplasmic acetyl-coA availability.

ORGANISM(S): Mus Musculus

SUBMITTER: Michael MacCoss

PROVIDER: PXD023309 | panorama | Thu Dec 24 00:00:00 GMT 2020

REPOSITORIES: PanoramaPublic

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Project description:Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect. Liver samples were obtained from 36 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a mild-high-fat diet. 12 mice were sacrificed immediately after the adaptation phase (t=0). The other 24 mice received the mild-high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q) for 12 weeks.

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Lysosomal targetomics in ghrKO mice reveals a role for chaperone-mediated autophagy in shaping the nucleocytosolic acetyl-coA production pathway

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