Dataset Information

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice

ABSTRACT: Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige activation and provides a potentialnovel targeted approach for the treatment of metabolic diseases.

ORGANISM(S): Mus Musculus

SUBMITTER: Yong Chen

PROVIDER: PXD055014 | iProX | Fri Aug 16 00:00:00 BST 2024

REPOSITORIES: iProX

ACCESS DATA

Publications

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.

Yang Min M Ge Jing J Liu Yu-Lian YL Wang Huan-Yu HY Wang Zhi-Han ZH Li Dan-Pei DP He Rui R Xie Yu-Yu YY Deng Hong-Yan HY Peng Xue-Min XM Wang Wen-She WS Liu Jia-Dai JD Zhu Zeng-Zhe ZZ Yu Xue-Feng XF Maretich Pema P Kajimura Shingo S Pan Ru-Ping RP Chen Yong Y

Nature communications 20240905 1

Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation a ...[more]

PMID: 39232011

Similar Datasets

Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model) Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505 ], (ii) time-course model [ BIOMD0000000506 ]. This model corresponds to the steady-state model. This model is described in the article: Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM. PLoS Comput Biol. 2013;9(8):e1003186. Abstract: Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration. This model is hosted on BioModels Database and identified by: BIOMD0000000505 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (time-course model) Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505 ], (ii) time-course model [ BIOMD0000000506 ]. This model corresponds to the time-course model. This model is described in the article: Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM. PLoS Comput Biol. 2013;9(8):e1003186. Abstract: Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration. This model is hosted on BioModels Database and identified by: BIOMD0000000506 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice

Publications

Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets