• Integrative Medicine Research
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• 제2권4호
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• pp.131-138
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• 2013

The skeletal muscle in our body is a major site for bioenergetics and metabolism during exercise. Carbohydrates and fats are the primary nutrients that provide the necessary energy required to maintain cellular activities during exercise. The metabolic responses to exercise in glucose and lipid regulation depend on the intensity and duration of exercise. Because of the increasing prevalence of obesity, recent studies have focused on the cellular and molecular mechanisms of obesity-induced insulin resistance in skeletal muscle. Accumulation of intramyocellular lipid may lead to insulin resistance in skeletal muscle. In addition, lipid intermediates (e.g., fatty acyl-coenzyme A, diacylglycerol, and ceramide) impair insulin signaling in skeletal muscle. Recently, emerging evidence linking obesity-induced insulin resistance to excessive lipid oxidation, mitochondrial overload, and mitochondrial oxidative stress have been provided with mitochondrial function. This review will provide a brief comprehensive summary on exercise and skeletal muscle metabolism, and discuss the potential mechanisms of obesity-induced insulin resistance in skeletal muscle.

• 약학회지
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• 제41권6호
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• pp.789-796
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• 1997

The purpose of this study was to determine the effect of sulfinpyrazone on fumonisin $B_1$-induced elevation of free sphingoid bases in LLC-$PK_1$ cells. Fumonis ins are a family of mycotoxins produced by the fungi Fusarium moniliforme which is common contaminant in corn. Fumonisins are also potent inhibiors of sphingosine and sphinganine N-acyltransferases (ceramide synthases), key enzymes in sphingolipid metabolism resulting in the elevation of free sphinganine. The cytosolic concentration of fumonisin B1 was known to be closely proportional to the elevation of free sphinganine in LLC-PK1 cells [Yoo, H.-S., Norred, W.P., Wang, E., Merrill, A.H., Jr., and Riley, R.T. (1992) Toxicol. Appl.Pharmacol. 114. 9-15]. Sulfinpyrazone, an anion transport inhibitor, reduced the elevated level of free sphinganine resulting from fumonisin B1 inhibition of de novo sphingolipid biosynthesis. Fumonisin B1 at a concentration of 20${\mu}$M showed approximately 120pmol/$10^6$ cells relative to 3-10pmol/$10^6$ cells in control cultures, and sulfinpyrazone at a concentration of 200${\mu}$M partially reversed the increased level of free sphinganine induced by fumonisin $B_1$ down to normal level after exposure to fumonisin $B_1$ for 8 to 24hr. However, the reduced effect of sulfinpyrazone on the fumonisin $B_1$-induced elevation of intracellular sphinganine was not shown after 24hr. Fumonisin $B_1$ exposure to LLC-PK1 cells for 36 and 48hr showed approximately 74 and 80pmol per $10^6$ cells relative to 82 and 76pmol,respectively, in fumonisin $B_1$ plus sulfinpyrazone-treated cultures. Sulfinpyrazone-induced less elevation of free sphinganine in confluent cells after exposure to fumonisin $B_1$ suggested that either sulfinpyrazone may block the availability of fumonisin $B_1$ to cells or act on the fumonisin $B_1$ interaction with ceramide synthase.

• Archives of Pharmacal Research
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• 제28권3호
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• pp.311-318
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• 2005

Oxidative stress has been reported to elevate ceramide level during cell death. The purpose of the present study was to modulate cell death in relation to cellular glutathione (GSH) level and GST (glutathione S-transferase) expression by regulating the sphingolipid metabolism. LLC­PK1 cells were treated with H$_2$O$_2$ in the absence of serum to induce cell death. Subsequent to exposure to H$_2$O$_2$, LLC-PK1 cells were treated with desipramine, sphingomyelinase inhibitor, and N-acetylcysteine (NAC), GSH substrate. Based on comparative visual observation with H202-treated control cells, it was observed that 0.5 $\mu$M of desipramine and 25 $\mu$M of NAC exhibited about 90 and $95\%$ of cytoprotection, respectively, against H$_2$O$_2$-induced cell death. Desipramine and NAC lowered the release of LDH activity by 36 and $3\%$ respectively, when compared to $71\%$ in H$_2$O$_2$-exposed cells. Cellular glutathione level in 500 $\mu$M H202-treated cells was reduced to 890 pmol as compared to control level of 1198 pmol per mg protein. GST P1-1 expression was decreased in H$_2$O$_2$-treated cells compared to healthy normal cells. In conclusion, it has been inferred that H$_2$O$_2$-induced cell death is closely related to cellular GSH level and GST P1-1 expression in LLC-PK1 cells and occurs via ceramide elevation by sphingomyelinase activation.

• Molecules and Cells
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• 제43권5호
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• pp.419-430
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• 2020

The liver is an important organ in the regulation of glucose and lipid metabolism. It is responsible for systemic energy homeostasis. When energy need exceeds the storage capacity in the liver, fatty acids are shunted into nonoxidative sphingolipid biosynthesis, which increases the level of cellular ceramides. Accumulation of ceramides alters substrate utilization from glucose to lipids, activates triglyceride storage, and results in the development of both insulin resistance and hepatosteatosis, increasing the likelihood of major metabolic diseases. Another sphingolipid metabolite, sphingosine 1-phosphate (S1P) is a bioactive signaling molecule that acts via S1P-specific G protein coupled receptors. It regulates many cellular and physiological events. Since an increase in plasma S1P is associated with obesity, it seems reasonable that recent studies have provided evidence that S1P is linked to lipid pathophysiology, including hepatosteatosis and fibrosis. Herein, we review recent findings on ceramides and S1P in obesity-mediated liver diseases and the therapeutic potential of these sphingolipid metabolites.

• 운동영양학회지
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• 제23권2호
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• pp.1-6
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• 2019

[Purpose] Strenuous exercise often induces skeletal muscle damage, which results in impaired performance. Sphingolipid metabolism contributes to various cellular processes, including apoptosis, stress response, and inflammation. However, the relationship between exercise-induced muscle damage and ceramide (a key component of sphingolipid metabolism), is rarely studied. The present study aimed to explore the regulatory role of sphingolipid metabolism in exercise-induced muscle damage. [Methods] Mice were subjected to strenuous exercise by treadmill running with gradual increase in intensity. The blood and gastrocnemius muscles (white and red portion) were collected immediately after and 24 h post exercise. For 3 days, imipramine was intraperitoneally injected 1 h prior to treadmill running. [Results] Interleukin 6 (IL-6) and serum creatine kinase (CK) levels were enhanced immediately after and 24 h post exercise (relative to those of resting), respectively. Acidic sphingomyelinase (A-SMase) protein expression in gastrocnemius muscles was significantly augmented by exercise, unlike, serine palmitoyltransferase-1 (SPT-1) and neutral sphingomyelinase (N-SMase) expressions. Furthermore, imipramine (a selective A-SMase inhibitor) treatment reduced the exercise-induced CK and IL-6 elevations, along with a decrease in cleaved caspase-3 (Cas-3) of gastrocnemius muscles. [Conclusion] We found the crucial role of A-SMase in exercise-induced muscle damage.

• Journal of Nutrition and Health
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• 제48권4호
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• pp.319-326
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• 2015

본 연구에서는 기니피그에 8주간 필수지방산 결핍 식이 공급에 의해 표피 과증식을 유도한 후 계속된 2주간의 보라지유 또는 홍화유 식이 공급에 의한 과증식 억제 및 Cer, GlcCer, SM의 표피 함량 및 세라마이드 대사 관련 효소들의 단백질 발현 변화를 정상대조군인 BO군 및 필수지방산 결핍 군인 HCO군과 비교하였으며 그 결과는 다음과 같다. 1. 8주간의 필수지방산 결핍 식이 공급 후 계속된 2주간의 보라지유 식이 공급 (HCO + BO군)은 2주간의 홍화유 식이 공급에 (HCO + SO군) 비해 더욱 현저히 표피 과증식을 억제하였다. 2. 10주간 필수지방산 결핍식이를 공급한 HCO군은 정상대조군인 BO군에 비해 Cer의 총 함량 및 Cer1/2/5/6/7, GlcCer-A/B의 함량이 유의적으로 감소되었다. HCO + BO군의 Cer과 GlcCer의 총 함량 및 Cer1/2, GlcCer-A/B, SM1의 함량은 HCO군에 비해 유의적으로 증가한 반면 HCO + SO군의 이들 함량은 HCO군과 유사하였다. GlcCer-C/D, SM의 총 함량 및 SM 2/3의 함량은 군간 변화가 없었다. 3. HCO군에서는 GCase 발현이 감소한 반면 HCO + BO군에서는 현저히 증가하였다. HCO + SO군의 aSMase의 단백질 발현이 HCO군에 비해 유의적으로 증가하였으나 aCDase의 발현 또한 다른 군에 비해 현저히 증가하였다. HCO + BO군과 HCO + SO군 모두 SPT의 단백질 발현이 HCO군에 비해 유의적으로 증가하였다. 결론적으로 표피 과증식이 유도된 기니피그에 보라지유 식이 공급은 GlcCer-A/B을 포함하는 GlcCer 총 함량, SM1 및 GCase의 발현 증가와 더불어 Cer1/2를 포함하는 Cer 총 함량을 증가시켜 궁극적으로 표피 과증식을 현저히 억제하였다.

• Biomolecules & Therapeutics
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• 제22권2호
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• pp.83-92
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• 2014

Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.

• BMB Reports
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• 제42권8호
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• pp.475-481
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• 2009

Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer's disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second major mechanism of cognitive impairment has been linked to obesity and Type 2 diabetes (T2DM). Human and experimental animal studies revealed that neurodegeneration associated with peripheral insulin resistance is likely effectuated via a liver-brain axis whereby toxic lipids, including ceramides, cross the blood brain barrier and cause brain insulin resistance, oxidative stress, neuro-inflammation, and cell death. In essence, there are dual mechanisms of brain insulin resistance leading to AD-type neurodegeneration: one mediated by endogenous, CNS factors; and the other, peripheral insulin resistance with excess cytotoxic ceramide production.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.69.1-69.1
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• 2003

Fumonisins are a family of mycotoxins produced from Fusarium verticillioides. Most of fumonisin B1 (FB1) toxicities can be explained by its ability to alter sphingolipid metabolism by inhibiting ceramide synthase. At least, the elevation in dihydrosphingosine (DHS) mediates the earliest toxicity of FB1. Some tissues such as kidney and liver, may be most affected by FB1 because they shows high rates of de novo sphingolipid synthesis. Recent review on FB1 toxicity by A.H. Merrill Jr. et al. suggested the possible role of dihydrosphingosine 1-phosphate (dihydroS1P), which sometimes elevated in cell- or tissue specific manners. (omitted)

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.110.1-110.1
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• 2003

Fumonisins are specific inhibitors of ceramide synthase in sphingolipid metabolism. Sphingolipids are biologically active lipid mediators in cellular physiology and involved in cell signaling, growth, transformation, angiogenesis and differentiation. The objective of this study was to determine the effect of fumonisin B1 on $Na^+, \;K^+$-pump activity when fumonisin B1 was exposed to LLC-PK1 cells. Fumonisin B1 elevated free sphingoid bases and their 1-phosphates, while total complex sphingolipids were depleted at 20$\mu$M fumonisin B1 during the 3 day exposure. (omitted)