Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment

AbstractThe peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design.

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Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment

10.1101/2021.09.04.458904 ◽

2021 ◽

Author(s):

Le Thi My Le ◽

James Robert Thompson ◽

Phuoc Xuan Dang ◽

Janarjan Bhandari ◽

Amer Alam

Keyword(s):

Fatty Acid ◽

Cellular Fatty Acid ◽

Dependent Manner ◽

Structural Elements ◽

Membrane Bilayer ◽

Long Chain Fatty Acid ◽

Structure Based Drug Design ◽

Fatty Acid Transporter ◽

Acyl Chains ◽

Lipid Environment

AbstractThe peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to cellular fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive nervous system demyelination, and neurological impairments including the potentially fatal disease X-linked adrenoleukodystrophy (X-ALD). Molecular details underlying substrate recognition and transport by ABCD1 are poorly understood. Here we determined cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution that reveal key details of its transmembrane cavity and ATP dependent conformational transitions. We identify structural elements distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Together, our data support a transport mechanism where only the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane cavity while the acyl chains extend out into the surrounding membrane bilayer, help rationalize disease causing mutations, and provide a framework for ABCD1 targeted structure-based drug design.

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Elevated Glucose and Insulin Levels Decrease DHA Transfer across Human Trophoblasts via SIRT1-Dependent Mechanism

Nutrients ◽

10.3390/nu12051271 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1271

Author(s):

Jay S. Mishra ◽

Hanjie Zhao ◽

Sari Hattis ◽

Sathish Kumar

Keyword(s):

Fatty Acid ◽

High Glucose ◽

Molecular Mechanisms ◽

Sirtuin 1 ◽

Dependent Manner ◽

Sirt1 Expression ◽

Insulin Levels ◽

Triglyceride Accumulation ◽

Elevated Glucose ◽

Fatty Acid Transporter

Gestational diabetes mellitus (GDM) results in reduced docosahexaenoic acid (DHA) transfer to the fetus, likely due to placental dysfunction. Sirtuin-1 (SIRT1) is a nutrient sensor and regulator of lipid metabolism. This study investigated whether the high glucose and insulin condition of GDM regulates DHA transfer and expression of fatty acid transporters and if this effect is related to SIRT1 expression and function. Syncytialized primary human trophoblasts were treated with and without glucose (25 mmol/L) and insulin (10−7 mol/L) for 72 h to mimic the insulin-resistance conditions of GDM pregnancies. In control conditions, DHA transfer across trophoblasts increased in a time- and dose-dependent manner. Exposure to GDM conditions significantly decreased DHA transfer, but increased triglyceride accumulation and fatty acid transporter expression (CD36, FABP3, and FABP4). GDM conditions significantly suppressed SIRT1 mRNA and protein expression. The SIRT1 inhibitor decreased DHA transfer across control trophoblasts, and recombinant SIRT1 and SIRT1 activators restored the decreased DHA transport induced by GDM conditions. The results demonstrate a novel role of SIRT1 in the regulation of DHA transfer across trophoblasts. The suppressed SIRT1 expression and the resultant decrease in placental DHA transfer caused by high glucose and insulin levels suggest new insights of molecular mechanisms linking GDM to fetal DHA deficiency.

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Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice

10.2337/figshare.16745977 ◽

2021 ◽

Author(s):

Wei Sun ◽

Tao Nie ◽

Kuai Li ◽

Wenjie Wu ◽

Qiaoyun Long ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Chain Fatty Acid ◽

Metabolic Phenotype ◽

Fibroblast Growth Factor 21 ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Long Chain Fatty Acid ◽

Molecular Events ◽

Long Chain

Background & Aims Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism. Approach & Results Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Conclusions Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

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Crystal Structure of the Long-Chain Fatty Acid Transporter FadL

Science ◽

10.1126/science.1097524 ◽

2004 ◽

Vol 304 (5676) ◽

pp. 1506-1509 ◽

Cited By ~ 131

Author(s):

B. van den Berg

Keyword(s):

Crystal Structure ◽

Fatty Acid ◽

Chain Fatty Acid ◽

Long Chain Fatty Acid ◽

Fatty Acid Transporter ◽

Acid Transporter ◽

Long Chain

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PUCHI regulates very long chain fatty acid biosynthesis during lateral root and callus formation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906300116 ◽

2019 ◽

Vol 116 (28) ◽

pp. 14325-14330 ◽

Cited By ~ 5

Author(s):

Duy-Chi Trinh ◽

Julien Lavenus ◽

Tatsuaki Goh ◽

Yohann Boutté ◽

Quentin Drogue ◽

...

Keyword(s):

Cell Proliferation ◽

Fatty Acid ◽

Lateral Root ◽

Time Course ◽

Callus Formation ◽

Chain Fatty Acid ◽

Dependent Manner ◽

Long Chain Fatty Acid ◽

Lateral Root Primordia ◽

Long Chain

Lateral root organogenesis plays an essential role in elaborating plant root system architecture. InArabidopsis, the AP2 family transcription factor PUCHI controls cell proliferation in lateral root primordia. To identify potential targets of PUCHI, we analyzed a time course transcriptomic dataset of lateral root formation. We report that multiple genes coding for very long chain fatty acid (VLCFA) biosynthesis enzymes are induced during lateral root development in a PUCHI-dependent manner. Significantly, several mutants perturbed in VLCFA biosynthesis show similar lateral root developmental defects aspuchi-1. Moreover,puchi-1roots display the same disorganized callus formation phenotype as VLCFA biosynthesis-deficient mutants when grown on auxin-rich callus-inducing medium. Lipidomic profiling ofpuchi-1roots revealed reduced VLCFA content compared with WT. We conclude that PUCHI-regulated VLCFA biosynthesis is part of a pathway controlling cell proliferation during lateral root and callus formation.

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Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

Nature Communications ◽

10.1038/s41467-021-25398-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Feng Wang ◽

Yuxi Dai ◽

Xufeng Zhu ◽

Qilong Chen ◽

Huanhu Zhu ◽

...

Keyword(s):

Fatty Acid ◽

Membrane Lipids ◽

Acyl Chain ◽

Behenic Acid ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase ◽

C Elegans ◽

Acyl Chains ◽

Membrane Budding ◽

Lifespan Regulation

AbstractThe contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.

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TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase

eLife ◽

10.7554/elife.71220 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jing Xue ◽

Yan Han ◽

Hamid Baniasadi ◽

Weizhong Zeng ◽

Jimin Pei ◽

...

Keyword(s):

Fatty Acid ◽

Membrane Protein ◽

Coenzyme A ◽

Transmembrane Domain ◽

Coiled Coil ◽

Structural Features ◽

Mechanosensitive Channel ◽

Transmembrane Helices ◽

Long Chain Fatty Acid ◽

Fatty Acid Elongase

TMEM120A, also named as TACAN, is a novel membrane protein highly conserved in vertebrates and was recently proposed to be a mechanosensitive channel involved in sensing mechanical pain. Here we present the single particle cryo-EM structure of human TMEM120A which forms a tightly packed dimer with extensive interactions mediate by the N-terminal coiled coil domain (CCD), the C-terminal transmembrane domain (TMD), and the re-entrant loop between the two domains. The TMD of each TMEM120A subunit contains six transmembrane helices (TMs) and has no clear structural feature of a channel protein. Instead, the six TMs form an α-barrel with a deep pocket where a coenzyme A (CoA) molecule is bound. Intriguingly, some structural features of TMEM120A resemble those of elongase for very long-chain fatty acid (ELOVL) despite low sequence homology between them, pointing to the possibility that TMEM120A may function as an enzyme for fatty acid metabolism, rather than a mechanosensitive channel.

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