ABCD2 Alters Peroxisome Proliferator-Activated Receptor<i>α</i>Signaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

Liu, Xiaoxi; Liu, Jingjing; Liang, Shuang; Schlüter, Agatha; Fourcade, Stéphane; Aslibekyan, Stella; Pujol, Aurora; Graf, Gregory A.

doi:10.1124/mol.114.092742

Cited by 7 publications

(7 citation statements)

References 56 publications

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“…SNPs in genes in the common variant analysis with P < 1 × 10 ‐5 or q < 0.2 in the rare variant analysis were compared to gene expression results in wild‐type C57BL/6J mice fed vehicle control or fenofibrate for replication (REP1). Fifty‐seven genes overlapped between the two studies, and 10 were significant in REP1 ( q < 0.3; Mcm6 , Smad3 , Dcun1d4 , Hecw2 , Mipep , Ipo11 , R3hdm1 , Foxp1 , Stx8 , and Mapk10 ; Table ).…”

Section: Resultsmentioning

confidence: 99%

“…We investigated gene expression changes in wild‐type C57BL/6J mice administered fenofibrate compared with mice administered vehicle control, as described by Liu et al . to provide additional validation for common and rare variant associations with fenofibrate lipid response identified (REP1).…”

Section: Methodsmentioning

confidence: 99%

“…We investigated gene expression changes in wild-type C57BL/6J mice administered fenofibrate compared with mice administered vehicle control, as described by Liu et al 20 to provide additional validation for common and rare variant associations with fenofibrate lipid response identified (REP1). To maximize the likelihood of finding genes with expression changes due to fenofibrate exposure, we expanded the genes chosen for evaluation to include those with common variant associations P < 1 3 10 -5 , where the variants were annotated as being in genes according to the National Center for Biotechnology Information database using the rsnps package, 50 and genes with q < 0.2 in the rare variant tests.…”

Section: Mouse Gene Expression Validationmentioning

confidence: 99%

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Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Rotroff

Pijut

Marvel

et al. 2017

Clin Pharma and Therapeutics

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Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Mouse Gene Expression Validationmentioning

confidence: 99%

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Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Rotroff

Pijut

Marvel

et al. 2017

Clin Pharma and Therapeutics

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“…In spite of treatment of DIO rodents with fenofibrate has been reported to suppress weight gain and reduce visceral adiposity ameliorating metabolic disorder, the mechanisms by which fenofibrate exerts these effects have yet to be completely elucidated (Chaput, Saladin, Silvestre, & Edgar, ; Goto et al, ; Liu et al, ; Mancini et al, ; Rachid et al, ). The postulated mechanism involved in anti‐obesity effect of fenofibrate is a browning effect on subcutaneous fat depots (Rachid et al, ) via the increase in hepatic FGF21 (Goto et al, ).…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

Frias

Rocha

Mendonça

et al. 2017

Journal Cellular Physiology

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The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

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“…ABCD2 plays a role in the degradation of long-chain saturated and omega 9monounsaturated fatty acids and in the synthesis of docosahexanoic acid (DHA) (Fourcade et al, 2009). The absence of ABCD2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling (Liu et al, 2014). Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse X-linked Adrenoleukodystrophy model (Fourcade et al, 2010) .…”

Section: Differential Expression Analysis Of Liver Transcriptomesmentioning

confidence: 99%

Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice

Guo

Mao

Yan

et al. 2020

PeerJ

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Background Oxidative-stress (OS) was causal in the development of cell dysfunction and insulin resistance. Streptozotocin (STZ) was an alkylation agent that increased reactive oxygen species (ROS) levels. Here we aimed to explore the oxidative-stress and related RNAs in the liver of STZ-induced diabetic mice. Methods RNA-sequencing was performed using liver tissues from STZ induced diabetic mice and controls. Pathway and Gene Ontology (GO) analyses were utilized to annotate the target genes. The differentially expressed RNAs involved in the peroxisome pathway were validated by qRT-PCR. The glucose metabolite and OS markers were measured in the normal control (NC) and STZ-induced diabetic mellitus (DM) group. Results The levels of serum Fasting insulin, HbA1c, Malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α) were significant higher in DM groups than NC group, while SOD activity decreased significantly in DM groups. We found 416 lncRNAs and 910 mRNAs were differentially expressed in the STZ-induced diabetic mice compared to the control group. OS associated RNAs were differentially expressed in the liver of STZ-induced diabetic mice. Conclusion This study confirmed that the OS was increased in the STZ-induced DM mice as evidenced by the increase of lipid peroxidation product MDA and 8-iso-PGF2α, identified aberrantly expressed lncRNAs and mRNAs in STZ-induced diabetic mice.

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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

Cited by 7 publications

References 56 publications

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

Changes of liver transcriptome profiles following oxidative stress in streptozotocin-induced diabetes in mice

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