The effect of enterolactone on sphingolipid pathway and hepatic insulin resistance development in HepG2 cells

Charytoniuk, Tomasz; Iłowska, Nicoletta; Berk, Klaudia; Drygalski, Krzysztof; Chabowski, Adrian; Konstantynowicz-Nowicka, Karolina

doi:10.1016/j.lfs.2018.11.044

Cited by 20 publications

(15 citation statements)

References 31 publications

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“…Noteworthy, in the group incubated with COM20 alone, we reported a substantially increased concentration of CER, whereas in the study conducted by Charytoniuk et al an increased content of SFA, not CER, after incubation with enterolactone alone was reported. This suggests that coumestrol, similarly to enterolactone, may exert various effects on the sphingolipid accumulation, depending on the presence or absence of palmitate excess and cell type [9]. As observed in our study, increased accumulation of CER may be a result of increased expression of proteins involved in FFA uptake including FABPpm, FATP, and FAT/CD36.…”

Section: Discussionsupporting

confidence: 74%

“…Most studies were conducted on muscle tissue, whereas there are only limited data showing the correlation between increased accumulation of various sphingolipids and the development of insulin resistance in the liver. Thus, the mechanism and possible treatment methods of these particular alterations remain partially unknown [6,9,10]. Coumestrol (COM) is a potent, naturally occurring phytoestrogen that belongs to the coumestans family and is widely found in soybeans, legumes, and brussels sprouts [11].…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Coumestrol on Sphingolipid Signaling Pathway and Insulin Resistance Development in Primary Rat Hepatocytes

et al. 2021

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Coumestrol is a phytoestrogen widely known for its anti-diabetic, anti-oxidant, and anti-inflammatory properties. Thus, it gets a lot of attention as a potential agent in the nutritional therapy of diseases such as obesity and type 2 diabetes. In our study, we evaluated whether coumestrol affects insulin resistance development via the sphingolipid signaling pathway in primary rat hepatocytes. The cells were isolated from the male Wistar rat's liver with the use of collagenase perfusion. Next, we incubated the cells with the presence or absence of palmitic acid and/or coumestrol. Additionally, some groups were incubated with insulin. The sphingolipid concentrations were assessed by HPLC whereas the expression of all the proteins was evaluated by Western blot. Coumestrol markedly reduced the accumulation of sphingolipids, namely, ceramide and sphinganine through noticeable inhibition of the ceramide de novo synthesis pathway in insulin-resistant hepatocytes. Moreover, coumestrol augmented the expression of fatty acid transport proteins, especially FATP5 and FAT/CD36, which also were responsible for excessive sphingolipid accumulation. Furthermore, coumestrol altered the sphingolipid salvage pathway, which was observed as the excessive deposition of the sphingosine-1-phosphate and sphingosine. Our study clearly showed that coumestrol ameliorated hepatic insulin resistance in primary rat hepatocytes. Thus, we believe that our study may contribute to the discovery of novel preventive and therapeutic methods for metabolic disorders.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

The Influence of Coumestrol on Sphingolipid Signaling Pathway and Insulin Resistance Development in Primary Rat Hepatocytes

et al. 2021

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Section: Effects Of Female Sex Hormones Oral Contraceptives and mentioning

confidence: 99%

“…Supplementation with enterolactone (ENL) in HepG2 cells showed a shift in the ω-6/ω-3 balance towards ω-6, as well as the increase in COX-2 and TNFα protein expressions [168], which led to the development of hepatic insulin resistance (IR) [169]. This consequence may be the result of an elevated intracellular ceramide accumulation caused by an increase in the de novo synthesis pathway, which led to enhanced apoptosis of HepG2 cells [169]. Additionally, the increase in intracellular ceramide content in cultures of primary rat hepatocytes is due to the pivotal role of transporters in facilitating fatty acid influx (FATP2), accumulation of ceramides (CERT), and export to the media (MTP and ABCA1) [170].…”

Section: Effects Of Female Sex Hormones Oral Contraceptives and mentioning

confidence: 99%

Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver

Soria-Jasso

Cariño-Cortés

Muñoz-Pérez

et al. 2019

IJMS

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The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate in digestion regulate the liver functions, but the sex hormones also exert a strong influence on this sexually dimorphic organ, via their receptors expressed in liver, in both health and disease. Besides, the liver modifies the actions of sex hormones through their metabolism and transport proteins. Given the anatomical position and physiological importance of liver, this organ is evidenced as an immune vigilante that mediates the systemic immune response, and, in turn, the immune system regulates the hepatic functions. Such feedback is performed by cytokines. Pro-inflammatory and anti-inflammatory cytokines are strongly involved in hepatic homeostasis and in pathological states; indeed, female sex hormones, oral contraceptives, and phytoestrogens have immunomodulatory effects in the liver and the whole organism. To analyze the complex and interesting beneficial or deleterious effects of these drugs by their immunomodulatory actions in the liver can provide the basis for either their pharmacological use in therapeutic treatments or to avoid their intake in some diseases.

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“…Palmitic acid (PA) is the most common saturated fatty acid found in animals and plants and is found in foods like meat, cheese, butter, and other dairy products. PA or palmitate at concentrations of 0.4 to 1.0 mM can induce a model of insulin resistance in cultured HepG2 cells [15–17]. Whether miRNAs are involved in the induction of resistance is not yet understood.…”

Section: Introductionmentioning

confidence: 99%

Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway

Huang

Chen

Wang

et al. 2019

BioMed Research International

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Obesity-related insulin resistance and high fatty acid concentrations occur during the development of type 2 diabetes mellitus. The role of high concentrations of plasma-free fatty acids is not fully understood. In this study, palmitic acid (PA, 0.8 mM for 24 h) induced the expression of miR-221 that bound to phosphoinositide 3-kinases (PI3K) mRNA to inhibit glucose uptake by HepG2 cells. Compared with controls, PA significantly decreased glucose uptake, increased insulin receptor substrate-2 (IRS-2) and miR-221 expression, and decreased phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter type 4 (GLUT4) mRNA expression. Luciferase reporter assay revealed that miR-221 binding inhibited PI3K expression. Transfection of HepG2 cells with an miR-221 mimic induced miR-221 expression and inhibited the PI3K/AKT pathway. PA decreased glucose uptake in HepG2 cells by inducing the expression of miR-221, which bound to PI3K mRNA and suppressed PI3K/AKT signaling. miR-221 may be a novel target for preventing and treating obesity-induced insulin resistance.

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The effect of enterolactone on sphingolipid pathway and hepatic insulin resistance development in HepG2 cells

Cited by 20 publications

References 31 publications

The Influence of Coumestrol on Sphingolipid Signaling Pathway and Insulin Resistance Development in Primary Rat Hepatocytes

The Influence of Coumestrol on Sphingolipid Signaling Pathway and Insulin Resistance Development in Primary Rat Hepatocytes

Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver

Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway

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