Modulation of Insulin Secretion by Fatty Acyl Analogs

Las, Guy; Mayorek, Nina; Dickstein, Kobie; Bar‐Tana, Jacob

doi:10.2337/db06-0687

Cited by 10 publications

(6 citation statements)

References 56 publications

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“…Balb‐c/nude mice injected with 10 6 HT29 cells in the right thigh were divided into three groups fed either with powdered regular chow, 0.05% (W/W) M16ββ in powdered chow or 0.05% (W/W) Cl‐DICA in powdered chow. Doses were in the range previously used in rodents in vivo 15. Upon the appearance of tumors, the tumors were measured by calliper (Mitutoyo, Tokyo, Japan) once every 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…In analogy with(n‐3) PUFA, xenobiotic amphipathic mono acyl‐CoA thioesters of the MEDICA series [ e.g ., β,β'‐tetramethylhexadecanedioic, (CH 2 ) 10 [C(CH 3 ) 2 CH 2 COOH] 2 (M16ββ); γ,γ'‐tetramethyloctadocanedioic acid, (CH 2 ) 10 [C(CH 3 ) 2 CH 2 CH 2 COOH] 2 (M18γγ)]10, 11 specifically bind to HNF‐4α with affinities in the nanomolar range and potently suppress its transcriptional activity 12–14. In contrast to M16ββ and M18γγ, α,α'‐chloro analogs of the MEDICA series [ e.g ., α,α'‐tetrachlorotetradecanedioic acid, (CH 2 ) 10 [CCl 2 COOH] 2 (Cl‐DICA)] do not serve as substrates for ATP‐dependent CoA‐thioesterification and do not suppress HNF‐4α transcriptional activity 15. Since HNF‐4α gene transcription is negatively autoregulated by HNF‐4α,16 acyl‐CoA ligands may further affect the expression of HNF‐4α‐responsive genes by modulating HNF‐4α expression.…”

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confidence: 99%

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Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Schwartz¹,

Algamas-Dimantov²,

Hertz³

et al. 2008

Intl Journal of Cancer

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Hepatocyte nuclear factor‐4α (HNF‐4α) serves as target for fatty acid nutrients and xenobiotic amphipathic carboxylates and may account for the differential effects of dietary fatty acids on colorectal cancer (CRC). The putative role played by HNF‐4α in CRC has been verified here by evaluating the effect of HNF‐4α antagonists and HNF‐4α siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF‐4α ligand antagonists of the MEDICA series, namely, β,β'‐tetramethylhexadecanedioic acid (M16ββ) and γ,γ'‐tetramethyloctadocanedioic acid (M18γγ) as well as HNF‐4α siRNA are shown here to inhibit growth and proliferation of HT29 and Caco2 CRC cells, accompanied by increased subG1 cell population, downregulated PCNA, activation of caspase‐3, upregulation of Bak and cytoplasmic cytochrome‐c, and downregulation of Bcl‐2 resulting in apoptotic death. Inhibition of CRC growth with concomitant apoptosis was further confirmed in nude mice xenotransplanted with HT29 CRC cells. CRC suppression by HNF‐4α ligand antagonists and by HNF‐4α siRNA was accounted for by suppression of HNF‐4α transcription and protein expression. α,α'‐tetrachlorotetradecanedioic acid (Cl‐DICA), a MEDICA analogue that fails to suppress HNF‐4α, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF‐4α converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNF‐4α activity by natural or xenobiotic HNF‐4α ligand antagonists or by HNF‐4α siRNA may offer a treatment mode for CRC. © 2008 Wiley‐Liss, Inc.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Schwartz¹,

Algamas-Dimantov²,

Hertz³

et al. 2008

Intl Journal of Cancer

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“…The terms glucotoxicity, lipotoxicity and glucolipotoxicity have no generally accepted definition. In different studies, they refer to different combinations and concentrations of glucose and FA, FA chain length, FA saturation, and FA to albumin complexes [10], [11], [12], [13]. Clearly, excessive and non-physiological levels of glucose and FA, or saturated FA alone, induce ß-cell damage ultimately leading to apoptosis and cell death.…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species Stimulate Insulin Secretion in Rat Pancreatic Islets: Studies Using Mono-Oleoyl-Glycerol

et al. 2012

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Chronic exposure (24–72 hrs) of pancreatic islets to elevated glucose and fatty acid leads to glucolipoxicity characterized by basal insulin hypersecretion and impaired glucose-stimulated insulin secretion (GSIS). Our aim was to determine the mechanism for basal hypersecretion of insulin. We used mono-oleoyl-glycerol (MOG) as a tool to rapidly increase lipids in isolated rat pancreatic ß-cells and in the clonal pancreatic ß-cell line INS-1 832/13. MOG (25–400 µM) stimulated basal insulin secretion from ß-cells in a concentration dependent manner without increasing intracellular Ca2+ or O2 consumption. Like GSIS, MOG increased NAD(P)H and reactive oxygen species (ROS). The mitochondrial reductant ß-hydroxybutyrate (ß-OHB) also increased the redox state and ROS production, while ROS scavengers abrogated secretion. Diazoxide (0.4 mM) did not prevent the stimulatory effect of MOG, confirming that the effect was independent of the KATP-dependent pathway of secretion. MOG was metabolized to glycerol and long-chain acyl-CoA (LC-CoA), whereas, acute oleate did not similarly increase LC-CoA. Inhibition of diacylglycerol kinase (DGK) did not mimic the effect of MOG on insulin secretion, indicating that MOG did not act primarily by inhibiting DGK. Inhibition of acyl-CoA synthetase (ACS) reduced the stimulatory effect of MOG on basal insulin secretion by 30% indicating a role for LC-CoA. These data suggest that basal insulin secretion is stimulated by increased ROS production, due to an increase in the mitochondrial redox state independent of the established components of GSIS.

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“…To date, this metabolite has not been observed to be associated with obesity, insulin resistance or metabolic syndrome. However, a recent study of a long-chain fatty acid similar to FA26:1, but with four methyl groups attached to the chain (3,3,14,14-tetramethylhexadecanedioic acid) confirmed its hypolipemic and antidiabetic properties, as well as its modulating effect on insulin secretion (Mayorek et al, 1997;Las et al, 2006;Kalderon et al, 2012). Further studies are needed to confirm the similar properties of FA26:1; O2 and to decide whether it can be considered a marker of ALMS/BBS progression.…”

Section: Discussionmentioning

confidence: 99%

Serum metabolomics identified specific lipid compounds which may serve as markers of disease progression in patients with Alström and Bardet-Biedl syndromes

Jeziorny,

Pietrowska,

Sieminska

et al. 2023

Front. Mol. Biosci.

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Objectives: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are among the so-called ciliopathies and are associated with the development of multiple systemic abnormalities, including early childhood obesity and progressive neurodegeneration. Given the progressive deterioration of patients’ quality of life, in the absence of defined causal treatment, it seems reasonable to identify the metabolic background of these diseases and search for their progression markers. The aim of this study was to find metabolites characteristic to ALMS and BBS, correlating with clinical course parameters, and related to the diseases progression.Methods: Untargeted metabolomics of serum samples obtained from ALMS and BBS patients (study group; n = 21) and obese/healthy participants (control group; each of 35 participants; n = 70) was performed using LC-QTOF-MS method at the study onset and after 4 years of follow-up.Results: Significant differences in such metabolites as valine, acylcarnitines, sphingomyelins, phosphatidylethanolamines, phosphatidylcholines, as well as lysophosphatidylethanolamines and lysophosphatidylcholines were observed when the study group was compared to both control groups. After a follow-up of the study group, mainly changes in the levels of lysophospholipids and phospholipids (including oxidized phospholipids) were noted. In addition, in case of ALMS/BBS patients, correlations were observed between selected phospholipids and glucose metabolism parameters. We also found correlations of several LPEs with patients’ age (p < 0.05), but the level of only one of them (hexacosanoic acid) correlated negatively with age in the ALMS/BBS group, but positively in the other groups.Conclusion: Patients with ALMS/BBS have altered lipid metabolism compared to controls or obese subjects. As the disease progresses, they show elevated levels of lipid oxidation products, which may suggest increased oxidative stress. Selected lipid metabolites may be considered as potential markers of progression of ALMS and BBS syndromes.

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Modulation of Insulin Secretion by Fatty Acyl Analogs

Cited by 10 publications

References 56 publications

Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Reactive Oxygen Species Stimulate Insulin Secretion in Rat Pancreatic Islets: Studies Using Mono-Oleoyl-Glycerol

Serum metabolomics identified specific lipid compounds which may serve as markers of disease progression in patients with Alström and Bardet-Biedl syndromes

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