MEK–ERK Inhibition Corrects the Defect in VLDL Assembly in HepG2 Cells

Tsai, Julie; Qiu, Wei; Kohen-Avramoglu, Rita; Adeli, Khosrow

doi:10.1161/01.atv.0000249861.80471.96

Cited by 72 publications

(62 citation statements)

References 43 publications

(47 reference statements)

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“…ERK has already been shown to be induced by MCP-1 in Chinese hamster ovary cells and in smooth muscle cells 22 , and to be involved in MCP-1-mediated monocyte chemotaxis. 34 Interestingly, Tsai et al 21 have recently demonstrated that inhibition of ERK pathway in HepG2 cells led to an increase in ApoB secretion. Given that, in our model, ApoB secretion is diminished upon MCP-1 treatment in Huh-7 cells and that this phenomenon can be rescued by an ERK inhibitor, we hypothesize that lipid accumulation is partly due to a blockade of lipid secretion via the ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the involvement of ERK in lipid secretion has been reported in HepG2 cells. 21 In addition, MCP-1 has been shown to activate MAPK pathways. 22,23 To determine whether MCP-1-induced lipid accumulation was dependent on MAPK pathway activation, even in the absence of large amounts of CCR2, Huh-7 cells were treated with MCP-1 and PD98059, an ERK inhibitor, or SB203580, a p38 MAPK inhibitor (Fig.…”

Section: Of Human Scwat Explants Induces Significantmentioning

confidence: 99%

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Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

et al. 2008

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For many years, adipose tissue has been mainly considered as an inert reservoir for storing triglycerides. Since the discovery that adipocytes may secrete a variety of bioactive molecules (hormones, chemokines, and cytokines), an endocrine and paracrine role for white adipose tissue (WAT) in the regulation of energy balance and other physiological processes has been established, particularly with regard to brain and muscle. In contrast, little is known about the interactions of WAT with liver. Hence, we examined the effect of the secretory products of WAT on hepatocytes. Conditioned medium of human WAT explants induced significant steatosis in hepatocyte cell lines. Factor(s) responsible for the conditioned medium-induced steatosis were screened by a battery of blocking antibodies against different cytokines/chemokines shown to be secreted by WAT. In contrast to interleukin-8 and interleukin-6, the monocyte chemoattractant protein-1 was capable of inducing steatosis in hepatocytes in a time-dependent manner at concentrations similar to those found in conditioned medium. Incubation of conditioned medium with antimonocyte chemoattractant protein-1 antibodies prevented triglyceride accumulation. Investigation of the mechanism leading to the triglyceride accumulation showed that both a diminution of apolipoprotein B secretion and an increase in phosphoenolpyruvate carboxykinase messenger RNA may be involved. Conclusion: The monocyte chemoattractant protein-1 secreted by adipose tissue may induce steatosis not only recruiting macrophages but also acting directly on hepatocytes. (HEPATOLOGY 2008;48:799-807.)

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Section: Discussionmentioning

confidence: 99%

Section: Of Human Scwat Explants Induces Significantmentioning

confidence: 99%

Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

et al. 2008

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“…In cultured hepatocytes, levels of DGAT1 and DGAT2 mRNA are regulated by the MEK-ERK signaling pathway (95). Inhibition of this signaling pathway in HepG2 hepatoma cells increased DGAT1 and DGAT2 mRNA levels 2-and 4-fold, respectively, and stimulated VLDL secretion.…”

Section: Regulation Of Dgat Enzymesmentioning

confidence: 99%

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

908

782

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Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acylCoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.-Yen, C-L. E., S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese, Jr. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008. 49: 2283-2301. Supplementary key words triacylglycerolsTriacylglycerols (triglycerides) (TGs), a major type of neutral lipid, are a heterogeneous group of molecules with a glycerol backbone and three FAs attached by ester bonds. The physical and chemical properties of TG differ based on chain length and the degree to which their FAs are desaturated. TGs serve multiple important functions in living organisms. Chief among these, they are the major storage molecules of FA for energy utilization and the synthesis of membrane lipids. Because they are highly reduced and anhydrous, TGs store 6-fold more energy than the same amount of hydrated glycogen (1). In plants, TGs are a major component of seed oils, which are valuable resources for dietary consumption and industrial uses. TG from plants and microorganisms can also be used for biofuels. In animals, energy stores of TG are concentrated primarily in adipocytes, although TGs are also found prominently in myocytes, hepatocytes, enterocytes, and mammary epithelial cells. In addition to energy storage, TG synthesis in cells may protect them from the potentially toxic effects of excess FA. In the enterocytes and hepatocytes of most mammals, TGs are synthesized for the assembly and secretion of lipoproteins, which transport dietary and endogenously synthesized FA between tissues. Also, TGs in secreted lipids acts as a component of the skinʼs surface water barrier, and collections of TG in adipose tissue provide insulation for organisms.Although TGs are essential for normal physiology, the excessive accumulation of TG in human adipose tissue results in obesity and, in nonadipose tissues, is associated with organ dysfunction. For example, excessive TG deposition in skeletal muscle and the liver is associated with insulin resistance, in the liver with nonalcoholic steatohepatitis, and in the heart with cardiomyopathy (2, 3). Owing to worldwide increases in the p...

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“…In contrast, MAPK family members such as ERK exert protective and anti-apoptotic effects upon activation by an upstream kinase and regulate a number of major cellular functions, such as cell proliferation, differentiation and inflammation (Czaja et al, 2003). Furthermore, ERK activation is reported to decrease DGAT2 expression (Wang et al, 2010;Tsai et al, 2007). Increased JNK phosphorylation has been reported in steatosis and NASH model mice (Hirosumi et al, 2002).…”

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confidence: 99%

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

et al. 2012

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-Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

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MEK–ERK Inhibition Corrects the Defect in VLDL Assembly in HepG2 Cells

Cited by 72 publications

References 43 publications

Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

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