Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet

Moody, Laura; Xu, Guanying Bianca; Chen, Hong; Pan, Yuan Xiang

doi:10.1016/j.bbagrm.2018.12.009

Cited by 39 publications

(28 citation statements)

References 86 publications

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“…PPAR-α and its target gene carnitine palmitoyltransferase 1 (CPT-1) have a pivotal role in fatty acid oxidation in mitochondria, and the PPAR-α/CPT-1 pathway is important in the inhibition of DIO. HFD can recruit PPAR-α and stimulate hepatic CPT-1A [47]. However, our study found a reduction in PPAR-α levels in the SN and VTA in HFD mice.…”

Section: Discussioncontrasting

confidence: 71%

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Kao

Wei

Tsai

et al. 2019

IJMS

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Although several epidemiologic and animal studies have revealed correlations between obesity and neurodegenerative disorders, such as Parkinson disease (PD), the underlying pathological mechanisms of obesity-induced PD remain unclear. Our study aimed to assess the effect of diet-induced obesity on the brain dopaminergic pathway. For five months, starting from weaning, we gave C57BL/6 mice a high-fat diet (HFD) to generate an obese mouse model and investigate whether the diet reprogrammed the midbrain dopaminergic system. Tyrosine hydroxylase staining showed that the HFD resulted in fewer dopaminergic neurons in the substantia nigra (SN), but not the striatum. It also induced neuroinflammation, with increased astrogliosis in the SN and striatum. Dendritic spine density in the SN of HFD-exposed mice decreased, which suggested that prolonged HFD altered dopaminergic neuroplasticity. All three peroxisome proliferator-activated receptor (PPAR) subtype (PPAR-α, PPAR-β/δ, PPAR-γ) levels were significantly reduced in the SN and the ventral tegmental area of HFD mice when compared to those in controls. This study showed that a prolonged HFD induced neuroinflammation, suppressed PPAR levels, caused degeneration of midbrain dopaminergic neurons, and resulted in symptoms reminiscent of human PD. To our knowledge, this is the first study documenting the effects of an HFD on PPARs in dopaminergic neurons.

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Section: Discussioncontrasting

confidence: 71%

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Kao

Wei

Tsai

et al. 2019

IJMS

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“…Regarding the significance of transcriptional regulations, hepatic gene transfer of Cpt1a using adeno-associated viruses suppressed the progression of obesity in mice [32]. In addition, a higher expression level of Cpt1a was observed in HFD-fed rats than in those fed a control diet, which could be attributed to the epigenetic DNA methylation change [33,34]. In the present study, comparison of gene expression between the ND and HFD-fed mice revealed similar transcriptional regulation (Fig.…”

Section: Discussionsupporting

confidence: 69%

Anti-obesity effect of a hop-derived prenylflavonoid isoxanthohumol in a high-fat diet-induced obese mouse model

Fukizawa

Yamashita

Wakabayashi

et al. 2020

Bioscience of Microbiota, Food and Health

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We examined whether oral administration of a hop-derived prenylflavonoid isoxanthohumol (IX) would show anti-obesity activity and the underlying mechanism of the potential activity using a high-fat diet (HFD)-induced obese mouse model. Oral administration of 180 mg/kg IX for 8 weeks suppressed HFD-induced accumulation of visceral fat and body weight gain in mice. Simultaneously, IX changed the composition of the microbiome, as determined by a significant increase in the relative abundances of Akkermansia muciniphila, Blautia, and Escherichia coli. A. muciniphila accounted for 23% and 24% of the total microbiome in the HFD+60 mg/kg and 180 mg/kg IX groups, respectively, while it was undetectable in the normal diet (ND) and HFD groups. Similarly, Blautia accounted for 8% and 10% of the total microbiome in the HFD+60 mg/kg and 180 mg/kg IX groups, respectively, while it accounted for less than 1% in the ND and HFD groups. In contrast, a significant decrease in the relative abundance of Oscillospira was observed in the HFD+60 mg/kg and 180 mg/kg IX groups compared with the HFD group. We further examined the anti-obesity effect of IX using a germ-free (GF) mouse model to clarify the relationship between the microbiome and the effect of IX. IX showed no significant anti-obesity effect on fat accumulation and weight gain in GF mice. These results suggest that the anti-obesity effect of IX may involve microbial changes.

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“…3c). Recently, changes in the Cpt1a promoter epigenetic profile were reported in the livers of rats exposed to HFD, which supports the possibility that lipid metabolism can also have influence on the function and integrity of BBB 32 . Changes in Figure 6.…”

Section: Discussionmentioning

confidence: 62%

“…The transcriptional and post-transcriptional regulation of the Cpt1a in every living organism facilitate adaptation to the changing environment, especially to diet. Recently, Moody et al provided evidence for epigenetic regulation of Cpt1a by DNA methylation and histone modifications in liver of rats fed HFD 32 . The human study of blood samples from the great Dutch famine also showed regulation of Cpt1a by DNA methylation 33 .…”

Section: Resultsmentioning

confidence: 99%

“…Abbreviations: Cpt1a, carnitine palmitoyl transferase 1a with a p479l mutation; WT, wild type. www.nature.com/scientificreports/ histone H3 methylation significantly affected binding of the transcription factor PPARα to the Cpt1a promoter 32 . Moreover, acute hyperglycemia-due to an imbalanced glucose/lipid metabolism-has been shown to cause persistent epigenetic changes, including changes to Cpt1a 77 .…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

Trabjerg

Mørkholt

Lichota

et al. 2020

Sci Rep

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The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.

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Epigenetic regulation of carnitine palmitoyltransferase 1 (Cpt1a) by high fat diet

Cited by 39 publications

References 86 publications

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

Anti-obesity effect of a hop-derived prenylflavonoid isoxanthohumol in a high-fat diet-induced obese mouse model

Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models

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