Protein kinase D protects against oxidative stress-induced intestinal epithelial cell injury via Rho/ROK/PKC-δ pathway activation

Song, Jun; Li, Jing; Lulla, Andrew; Evers, B. Mark; Chung, Dai H.

doi:10.1152/ajpcell.00486.2005

Cited by 57 publications

(47 citation statements)

References 45 publications

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“…RIE-1 rat intestinal epithelial cells 35 were maintained in DMEM containing 2 mM L-glutamine, 4500 mg/L glucose and 10% FBS. FHs 74 Int cells were tested for authentication via STR profiling in April 2015 by Genetica DNA Laboratories (LabCorp Specialty Testing Group; Burlington, NC) using the commercially available PowerPlex® 16HS amplification kit (Promega Corporation) and GeneMapper ID v3.2.1 software (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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227

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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227

237

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“…In airway epithelial cells, inhibition with either Y-27632 or HA1077 induces membrane ruffling, loss of actin stress fibers, and apoptosis that can be blocked by inhibiting caspase function or by inhibiting protein synthesis [90]. Rho/ROCK activation also plays a pro-survival role during oxidative stress (H 2 O 2 )-induced intestinal epithelial cell injury via activation of PKCδ and PKD [129]. In anaplastic thyroid cancer cells, inhibition of Rho by lovastatin or inhibition of ROCK by Y27632 induces cytochrome c release, activation of caspases 3 and 9, and apoptosis which required de novo protein synthesis [154].…”

Section: In Vitro Evidencementioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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“…25 PKC␦ has been suggested to regulate PKD activity in intestinal epithelial cells. 26 Interestingly, in addition to PKC␦ phosphoryla- Figure 2. Inhibition of PKD phosphorylation reduces the diabetes induced augmentation of coronary LPL activity.…”

Section: Mechanism Of Activation Of Pkd In Hearts From Animals With Hmentioning

confidence: 99%

Protein Kinase D Is a Key Regulator of Cardiomyocyte Lipoprotein Lipase Secretion After Diabetes

Kim¹,

Wang²,

Puthanveetil³

et al. 2008

Circulation Research

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Abstract-The diabetic heart switches to exclusively using fatty acid (FA) for energy supply and does so by multiple mechanisms including hydrolysis of lipoproteins by lipoprotein lipase (LPL) positioned at the vascular lumen. We determined the mechanism that leads to an increase in LPL after diabetes. Diazoxide (DZ), an agent that decreases insulin secretion and causes hyperglycemia, induced a substantial increase in LPL activity at the vascular lumen. This increase in LPL paralleled a robust phosphorylation of Hsp25, decreasing its association with PKC␦, allowing this protein kinase to phosphorylate and activate protein kinase D (PKD), an important kinase that regulates fission of vesicles from the golgi membrane. Rottlerin, a PKC␦ inhibitor, prevented PKD phosphorylation and the subsequent increase in LPL. Incubating control myocytes with high glucose and palmitic acid (GluϩPA) also increased the phosphorylation of Hsp25, PKC␦, and PKD in a pattern similar to that seen with diabetes, in addition to augmenting LPL activity. In myocytes in which PKD was silenced or a mutant form of PKC␦ was expressed, high GluϩPA were incapable of increasing LPL. Moreover, silencing of cardiomyocyte Hsp25 allowed phorbol 12-myristate 13-acetate to elicit a significant phosphorylation of PKC␦, an appreciable association between PKC␦ and PKD, and a vigorous activation of PKD. As these cells also demonstrated an additional increase in LPL, our data imply that after diabetes, PKD control of LPL requires dissociation of Hsp25 from PKC␦, association between PKC␦ and PKD, and vesicle fission. Results from this study could help in restricting cardiac LPL translocation, leading to strategies that overcome contractile dysfunction after diabetes. Key Words: heat shock protein Ⅲ protein kinase C Ⅲ hyperglycemia Ⅲ hyperlipidemia Ⅲ vesicles C ardiac muscle has a high demand for energy and uses multiple substrates, including fatty acid (FA), carbohydrate, amino acids, and ketones. 1 Among these substrates, carbohydrate and FA are the major sources from which the heart derives most of its energy. In a normal heart, whereas glucose and lactate account for approximately 30% of energy provided to the cardiac muscle, 70% of ATP generation is through FA oxidation. 2 FA delivery and utilization by the heart involves: (1) release from adipose tissue and transport to the heart after complexing with albumin, 3 (2) provision through breakdown of endogenous cardiac triglyceride (TG) stores, 4 (3) internalization of whole lipoproteins, 5 and (4) hydrolysis of circulating TG-rich lipoproteins to FA by lipoprotein lipase (LPL) positioned at the endothelial surface of the coronary lumen. 6 The molar concentration of FA bound to albumin is Ϸ10-fold less than that of FA in lipoprotein-TG, 7 and LPL-mediated hydrolysis of circulating TG-rich lipoproteins to FA is suggested to be the principal source of FA for cardiac utilization. 8 Coronary endothelial cells do not synthesize LPL. 9 In the heart, this enzyme is produced in cardiomyocytes and subsequently se...

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Protein kinase D protects against oxidative stress-induced intestinal epithelial cell injury via Rho/ROK/PKC-δ pathway activation

Cited by 57 publications

References 45 publications

An obligatory role for neurotensin in high-fat-diet-induced obesity

An obligatory role for neurotensin in high-fat-diet-induced obesity

Rho kinase in the regulation of cell death and survival

Protein Kinase D Is a Key Regulator of Cardiomyocyte Lipoprotein Lipase Secretion After Diabetes

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