20-HETE Induces Hyperglycemia through the cAMP/PKA-PhK-GP Pathway

Lai, Guangrui; Wu, Jingjing; Liu, Xiaoliang; Zhao, Yanyan

doi:10.1210/me.2012-1139

Cited by 22 publications

(17 citation statements)

References 35 publications

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“…3). The CYP4F2 transgenic mice had elevated levels of 20-HETE, compared with the levels in the controls in the liver (0.55±0.1, vs. 0.17±0.05 ng/mg pro) and the kidney (0.70±0.13, vs. 0.37±0.14 ng/mg pro), as previously reported (15). The total DiHETE levels were markedly higher in the liver (7.92±1.71, vs. 2.74±0.6 ng/mg pro) and kidney (1.32±0.24, vs. 0.64±0.13 ng/mg pro) of the transgenic mice, compared with the wild-type control mice.…”

Section: Eicosanoid Quantification Using Lc-ms/ms Analysissupporting

confidence: 86%

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Zhang

Lai

Liu

et al. 2016

Molecular Medicine Reports

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Abstract. Arachidonic acid (AA) can be metabolized into 20-hydroxyeicosatetraenoic acid (20-HETE) by ω-hydroxylases, and epoxyeicosatrienoic acids (EETs) by epoxygenases. The effects of EETs in cardiovascular physiology are vasodilatory, anti-inflammatory and anti-apoptotic, which are opposite to the function to 20-HETE. However, EETs are not stable in vivo, and are rapidly degraded to the biologically less active metabolites, dihydroxyeicosatrienoic acids, via soluble epoxide hydrolase (sEH). Western blotting, reverse transcription-quantitative polymerase chain reaction and liquid chromatography tandem mass spectrometry were performed in order to determine target RNA and protein expression levels. In the present study, it was demonstrated that the disturbed renal 20-HETE/EET ratio in the hypertensive cytochrome P450 4F2 transgenic mice was caused by the activation of sEH and the repression of epoxygenase activity. In addition, 20-HETE showed an opposite regulatory effect on the endogenous epoxygenases in the liver and kidney. Given that 20-HETE and EETs have opposite effects in multiple disease, the regulation of their formation and degradation may yield therapeutic benefits.

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Section: Eicosanoid Quantification Using Lc-ms/ms Analysissupporting

confidence: 86%

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Zhang

Lai

Liu

et al. 2016

Molecular Medicine Reports

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“…In addition to the vascular system, Nowicki et al have reported that 20-HETE inhibited a cAMP-dependent pathway in the kidney of rats that consumed a potassium-deficient diet (33). By contrast, results from our previous study demonstrated that 20-HETE activated the cAMP pathway in the liver of CYP4F2 transgenic mice (34). In blood pressure regulation, 20-HETE exhibited both prohypertensive and antihypertensive actions through vasoconstriction and natriuresis.…”

Section: Disccusioncontrasting

confidence: 54%

20-Hydroxyeicosatetraenoic acid regulates the expression of Nedd4-2 in kidney and liver through a neddylation modification pathway

Zhao

Zhang

Lai

et al. 2017

Molecular Medicine Reports

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The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway. Nedd4‑2 expression is increased in the kidney and decreased in the liver of transgenic mice compared with wild‑type mice. Subsequently, co‑immunoprecipitation analysis indicated that Nedd4‑2 was modified by Nedd8, and the level of neddylation on Nedd4‑2 was reduced in the kidney and increased in the liver of transgenic mice compared with controls. In addition, sentrin‑specific protease 8 (Senp8), a deneddylation enzyme, is expressed higher in the kidney and lower in the liver of transgenic mice compared with wild‑type controls. The function of 20‑HETE on modulation of Nedd4‑2 were also confirmed in mouse M1 kidney and mouse NCTC1469 liver cell lines, and the function was restored by neddylation inhibitor MLN4924 Data from the present study demonstrated that 20‑HETE upregulated the expression of Nedd4‑2 in the kidney and downregulated expression in the liver through the neddylation modification pathway, at least partly, depending on the effects on Senp8 deneddylation.

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“…In addition to the formation of PGs, terminal hydroxylation of AA yields the potent vasoconstrictive and proinflammatory eicosanoid 20-HETE (25). 20-HETE can induce hyperglycemia through the cAMP/ PKA-PhK-GP pathway (39), and 20-HETE levels have been positively associated with liver cirrhosis (40). We found that the hepatic 20-HETE level was significantly reduced in CD36Tg mice, but it was restored to the WT level upon Dox treatment (Fig.…”

Section: Creation Of Cd36tg Mice That Overexpress Cd36 In the Livermentioning

confidence: 73%

“…In addition to the reduction of PGs, we showed that the hepatic level of 20-HETE was also decreased in the CD36Tg mice without affecting the level of the parent arachidonic acid. The decreased formation of 20-HETE may have also contributed to the overall improvement of metabolic function, because this arachidonic acid metabolite has been shown to induce hyperglycemia (39).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Garbacz

Miller

et al. 2016

Molecular and Cellular Biology

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The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome. Individuals with metabolic syndrome or type 2 diabetes are susceptible to nonalcoholic fatty liver disease (1) and disruption of hepatic glucose and glycogen homeostasis (2). Hepatic steatosis is defined as an excess accumulation of fat in hepatocytes. Previous reports suggested that fatty acid translocase (FAT/CD36) plays an important role in hepatic lipid homeostasis (3-6). CD36 is a multiligand class B scavenger receptor with high affinity for lipids and lipid-containing ligands. CD36 is known for its lipid uptake function in macrophages, skeletal muscle, and the heart. However, the role of CD36 in hepatic lipid metabolism is still not well understood, and the available evidence is often conflicting, partly due to the lack of a reliable in vivo liver-specific gain-of-function model to specifically evaluate the function of CD36 in the liver.The basal expression of CD36 in the liver is low; however, it is highly inducible by a high-fat diet (HFD) (3). The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7, 8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6, 9). On the other hand, recent reports suggested that CD36 signaling might actually be beneficial in preventing fatty live...

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20-HETE Induces Hyperglycemia through the cAMP/PKA-PhK-GP Pathway

Cited by 22 publications

References 35 publications

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

Alteration of epoxyeicosatrienoic acids in the liver and kidney of cytochrome P450 4F2 transgenic mice

20-Hydroxyeicosatetraenoic acid regulates the expression of Nedd4-2 in kidney and liver through a neddylation modification pathway

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

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