The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid

Liu, Jingjing; Liang, Shuang; Liu, Xiaoxi; Brown, John R.; Newman, Kylie E.; Sunkara, Manjula; Morris, Andrew J.; Bhatnagar, Saloni; Li, Xiang-An; Pujol, Aurora; Graf, Gregory A.

doi:10.1194/jlr.m022160

Cited by 21 publications

(19 citation statements)

References 32 publications

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“…In the absence of fibrates, D2 deficiency resulted in a modest, but significant increase in fasting glucose at the midpoint and end of the study, as well as reduced glucose tolerance. This is inconsistent with our previously published work in which differences in glycemic control were not observed in D2-deficient mice following high-fat feeding or when crossed onto the ob/ob background (Liu et al, 2012). However, it should be noted that the previous study used a 45% kCal high-fat diet as opposed to the 60% kCal diet.…”

Section: Discussioncontrasting

confidence: 56%

“…D1 and D2 appear to cooperate in monounsaturated C26:1v9 import (Fourcade et al, 2010) as serum levels of C22:1v9, a fatty acid associated with disruptions in lipid metabolism in rats and other species (Bremer and Norum, 1982), were elevated in fed and fasting states (Fourcade et al, 2009;Liu et al, 2010). The absence of D2 sensitized mice to dietary erucic acid, resulting in the rapid onset of obesity and insulin resistance (Liu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…D2 expression levels in liver are near the lower limit of reverse transcriptionpolymerase chain reaction (rtPCR) and immunoblotting detection, but are dramatically upregulated by PPARa agonists and in genetic and high-fat feeding obesity models (Berger et al, 1999;Liu et al, 2012). Although no functional peroxisome proliferator response element has been identified in the D2 promoter, the expression of D2 is induced by fibrate treatment and is PPARa dependent (Fourcade et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

Liu

Liang

et al. 2014

Mol Pharmacol

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Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) a ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARa signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.

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Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

Liu

Liang

et al. 2014

Mol Pharmacol

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“…ABCD2 knockout mice develop hepatic steatosis when exposed to an erucic acid (C22:1) enriched diet [133]. The underlying mechanism is thought to be related to the inability of the ABCD2-deficient adipocytes to degrade erucic acid.…”

Section: Other Peroxisomal Metabolites and Hepatocyte Dysfunctionmentioning

confidence: 99%

Hepatic dysfunction in peroxisomal disorders

Baes

Veldhoven

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, and dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remains unclear.

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“…D2 deficient adipose tissue showed an increase in the abundance of 20:1 and 22:1 fatty acids. When D2 deficient mice were challenged with dietary erucic acid (C20:1), they exhibited rapid onset of obesity, hepatic steatosis, and insulin resistance [9]. While these data support a key role for D2 in lipid metabolism, the function of D2 in adipose and its relationship to adipose peroxisome metabolism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue

Liu

Lester

et al. 2015

Biochemical and Biophysical Research Communications

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ATP-binding cassette transporter D2 (D2) is an ABC half transporter that is thought to promote the transport of very long-chain fatty acyl-CoAs into peroxisomes. Both D2 and peroxisomes increase during adipogenesis. Although peroxisomes are essential to both catabolic and anabolic lipid metabolism, their function, and that of D2, in adipose tissues remain largely unknown. Here, we investigated the D2 localization and the proteome of D2-containing organelles, in adipose tissue. Centrifugation of mouse adipose homogenates generated a fraction enriched with D2, but deficient in peroxisome markers including catalase, PEX19, and ABCD3 (D3). Electron microscopic imaging of this fraction confirmed the presence of D2 protein on an organelle with a dense matrix and a diameter of ∼200 nm, the typical structure and size of a microperoxisome. D2 and PEX19 antibodies recognized distinct structures in mouse adipose. Immunoisolation of the D2-containing compartment confirmed the scarcity of PEX19 and proteomic profiling revealed the presence of proteins associated with peroxisome, endoplasmic reticulum (ER), and mitochondria. D2 is localized to a distinct class of peroxisomes that lack many peroxisome proteins, and may associate physically with mitochondria and the ER.

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The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid

Cited by 21 publications

References 32 publications

ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

ABCD2 Alters Peroxisome Proliferator-Activated ReceptorαSignaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

Hepatic dysfunction in peroxisomal disorders

ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue

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