Inhibition of CYP4A Reduces Hepatic Endoplasmic Reticulum Stress and Features of Diabetes in Mice

Park, Edmond Changkyun; Kim, Kyung Sik; Hong, Yeonhee; Hwang, Jeong Won; Cho, Gun-Sik; Cha, Hye-Na; Han, Jin‐Kwan; Yun, Chul‐Ho; Park, Soyoung; Jang, Ik‐Soon; Lee, Zee-Won; Choi, Jong-Soon; Kim, Soohyun; Kim, Gun-Hwa

doi:10.1053/j.gastro.2014.06.039

Cited by 48 publications

(43 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The activity of CYP4A and CYP4F enzymes can be enhanced by peroxisome proliferators like fibrates (27,28), and fenofibrate has been shown to lower 1-deoxySA and 14,15-cisdeoxySO levels in the plasma of dyslipidemic patients (29). Thus, we inferred that CYP4A or CYP4F could potentially be involved in the downstream metabolism of 1-deoxySLs.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 87%

“…We hypothesized that CYP enzymes could be involved in the downstream metabolism of 1-deoxySLs, as these enzymes are hydroxylases of both endogenous and exogenous substrates. In particular, we considered the CYP4A and CYP4F sub-families, which are involved in fatty acid hydroxylation, as their activity is enhanced by peroxisome proliferators like fibrates (27,28), and fenofibrate has been shown to lower 1-deoxySA and 14,15-cis-deoxySO levels in the plasma of dyslipidemic patients (29). Thus, we inferred that members of the CYP4A or CYP4F subfamilies could be involved in the downstream metabolism of 1-deoxySLs.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

show abstract

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 87%

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…CYP4A, which also metabolizes long-chain fatty acids like CYP2E1, may be a major and more critical player than CYP2E1 in the development of insulin resistance and hepatic steatosis in the HFD-exposed diabetic mice since inhibition of CYP4A reduced hepatic ER stress, apoptosis, insulin resistance, and steatosis. In addition, the levels of CYP2E1 were down-regulated in these mice while CYP4A contents remained similar following HFD exposure for 10 weeks [126]. …”

Section: Nafld and Cyp2e1mentioning

confidence: 99%

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

Abdelmegeed

Choi

et al. 2017

CMP

View full text Add to dashboard Cite

Alcoholic fatty liver diseases (AFLD) and non-alcoholic fatty liver diseases (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regards to the pathophysiological mechanism and progression despite different causes. Oxidative stress-induced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD. Interestingly, CYP2E1 isoforms expressed in both endoplasmic reticulum (ER) and mitochondria, likely lead to the deleterious consequences in response to alcohol or in conditions of NAFLD after exposure to high fat diet (HFD) and in obesity and diabetes. Whether CYP2E1 in both ER and mitochondria work simultaneously or sequentially in various conditions and whether mitochondrial CYP2E1 may exert more pronounced effects on mitochondrial dysfunction in AFLD and NAFLD are unclear. The aims of this review are to briefly describe the role of CYP2E1 and resultant oxidative stress in promoting mitochondrial dysfunction and the development or progression of AFLD and NAFLD, to shed a light on the function of the mitochondrial CYP2E1 as compared with the ER-associated CYP2E1. We finally discuss translational research opportunities related to this field.

show abstract

“…In contrast, CYP4A proteins were upregulated in livers of mice with genetically induced and diet-induced diabetes. The inhibition of CYP4A in mice reduced hepatic endoplasmic reticulum stress, apoptosis, insulin resistance, and steatosis (65). In addition, CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo (66).…”

Section: Discussionmentioning

confidence: 97%

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

Chen

et al. 2016

Advances in Nutrition

View full text Add to dashboard Cite

Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes. Future areas of research to address current deficiencies in the understanding of these enzymes and their eicosanoid metabolites in various aspects of metabolic diseases are also discussed. Adv Nutr 2016;7:1122-8.

show abstract

Inhibition of CYP4A Reduces Hepatic Endoplasmic Reticulum Stress and Features of Diabetes in Mice

Cited by 48 publications

References 38 publications

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

Contact Info

Product

Resources

About