Effects of lovastatin on hepatic fatty acid metabolism

Guzmán, Manuel; Cortés, José Emilio; Castro, José María Albertos

doi:10.1007/bf02537075

Cited by 19 publications

(6 citation statements)

References 51 publications

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“…ACC produces malonyl-CoA substrate for fatty acyl CoA synthase (FAS), a committed enzyme for fatty acid biosynthesis [20]. Interestingly, a study showed that lovastatin enhances fatty acid biosynthesis in cultured hepatocytes by activating ACC [54]. Our study is thus consistent with the enhancement of ACC activity in SH-SY5Y cells by SIM as indicated by a decrease in its phosphorylation.…”

Section: Discussionsupporting

confidence: 87%

Simvastatin Induced Neurite Outgrowth Unveils Role of Cell Surface Cholesterol and Acetyl CoA Carboxylase in SH-SY5Y Cells

et al. 2013

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Statins are known to modulate cell surface cholesterol (CSC) and AMP-activated protein kinase (AMPK) in non-neural cells; however no study demonstrates whether CSC and AMPK may regulate simvastatin induced neuritogenesis (SIN). We found that simvastatin (SIM) maintains CSC as shown by Fillipin III staining, Flotillin-2 protein expression / localization and phosphorylation of various receptor tyrosine kinases (RTKs) in the plasma membrane. Modulation of CSC revealed that SIN is critically dependent on this CSC. Simultaneously, phospho array for mitogen activated protein kinases (MAPKs) revealed PI3K / Akt as intracellular pathway which modulates lipid pathway by inhibiting AMPK activation. Though, SIM led to a transient increase in AMPK phosphorylation followed by a sudden decline; the effect was independent of PI3K. Strikingly, AMPK phosphorylation was regulated by protein phosphatase 2A (PP2A) activity which was enhanced upon SIM treatment as evidenced by increase in threonine phosphorylation. Moreover, it was observed that addition of AMP analogue and PP2A inhibitor inhibited SIN. Bio-composition of neurites shows that lipids form a major part of neurites and AMPK is known to regulate lipid metabolism majorly through acetyl CoA carboxylase (ACC). AMPK activity is negative regulator of ACC activity and we found that phosphorylation of ACC started to decrease after 6 hrs which becomes more pronounced at 12 hrs. Addition of ACC inhibitor showed that SIN is dependent on ACC activity. Simultaneously, addition of Fatty acid synthase (FAS) inhibitor confirmed that endogenous lipid pathway is important for SIN. We further investigated SREBP-1 pathway activation which controls ACC and FAS at transcriptional level. However, SIM did not affect SREBP-1 processing and transcription of its target genes likes ACC1 and FAS. In conclusion, this study highlights a distinct role of CSC and ACC in SIN which might have implication in process of neuronal differentiation induced by other agents.

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Section: Discussionsupporting

confidence: 87%

Simvastatin Induced Neurite Outgrowth Unveils Role of Cell Surface Cholesterol and Acetyl CoA Carboxylase in SH-SY5Y Cells

et al. 2013

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“…Acetyl-CoA carboxylases (ACCs) enzymes are involved in the synthesis and oxidation of fatty acids and have been targeted for the treatment of metabolic diseases such as type 2 diabetes and dyslipidaemia 3 .The ACCs inhibition might be expected to decrease fatty acid synthesis and increasing fatty acid oxidation. Studies indicated that high fat diet stimulates ACC1 expression in the liver 6 and another, study indicated that lovastatin increases fatty acid biosynthesis in cultured hepatocytes by activating ACC 39 which are in agreement with our study, but the increase of enzyme expression was not significant (table 5). Some studies have shown that malonyl CoA not only controls fatty acid metabolism but also has an important signaling function through its allosteric inhibition of carnitine palmitoyltransferase 1.…”

Section: Discussionsupporting

confidence: 92%

“…FAS is an enzyme synthesis fatty acids 3 . A study in cultured hepatocytes showed that lovastatin increased fatty acid biosynthesis by activating ACC 44 . Our study indicated that ACC1 mRNA expression is decreased when G4 group is treated by HFD and 20 mg simvastatin (P> 0.05).…”

Section: Discussionmentioning

confidence: 99%

The Simvastatin Effect on Acetyl Coa Carboxylase1 and Fatty Acid Synthase Gene Expression in Rat Fed With High Fat Diets and Its Association With Fatty Acid Proportion and Concentration

Sepehri

Nezhadebrahimi

Marjani

et al. 2021

Bulletin of Pharmaceutical Sciences. Assiut

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The aim of study was to determine the effect of different dosages of simvastatin on gene expression of Acetyl CoA Carboxylase 1 (ACC1) and Fatty Acid Synthase (FAS) in Wister rat hepatic tissues fed with high fat diets (HFD) and its association with serum fatty acid proportion and concentration. Four groups of rats (G1 to G4) were included. ACC1 and FAS expressions were analyzed by Real time quantitative polymerase chain reaction. Fatty acid concentration was measured by gas chromatography. There were significant differences when G4 versus G3, G4 and G3 versus G1 and G4 and G3 versus G2 was compared for total fatty acid concentration. The proportion of oleic acid to stearic acid showed significant decrease when G4 versus G3, G4 versus G2 and G4 versus G1 groups were compared, but the proportion of stearic acid to palmitic acid, linoleic acid to oleic acid (G3 versus G4) and oleic acid to palmitic acid in G4 increased when compared to G1, G2 and G3 groups. Treatment with simvastatin significantly increases or decreases some fatty acid ratio, serum fatty acid and total fatty acid concentrations. We also found that HFD led to no significant differences in ACC1 and FAS mRNA expression. Simvastatin increases proportion of linoleic acid to oleic acid, oleic acid to palmitic acid and oleic acid to stearic acid. Thus, statin therapy may be considered in prevention of cardiovascular and myocardial risk.

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“…Because PPAR␣ controls cellular fatty acid ␤-oxidation, we speculate that the unexplained rise in LCFA oxidation activity by statins (40,49,50) is at least in part mediated via PPAR␣ activation. This hypothesis is strongly supported by the fact that the induction of ACO mRNA levels by simvastatin is fully suppressed in PPAR␣-null mice (Fig.…”

Section: Statin-mediated Induction Of L-fabp Gene Expression Is Disrumentioning

confidence: 98%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

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Effects of lovastatin on hepatic fatty acid metabolism

Cited by 19 publications

References 51 publications

Simvastatin Induced Neurite Outgrowth Unveils Role of Cell Surface Cholesterol and Acetyl CoA Carboxylase in SH-SY5Y Cells

Simvastatin Induced Neurite Outgrowth Unveils Role of Cell Surface Cholesterol and Acetyl CoA Carboxylase in SH-SY5Y Cells

The Simvastatin Effect on Acetyl Coa Carboxylase1 and Fatty Acid Synthase Gene Expression in Rat Fed With High Fat Diets and Its Association With Fatty Acid Proportion and Concentration

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

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