Short- and long-term effects of atorvastatin, lovastatin and simvastatin on the cellular metabolism of cholesteryl esters and VLDL secretion in rat hepatocytes

Isusi, Efrén; Aspichueta, Patricia; Liza, Mariana; Hernández, M. Luisa; Dı́az, Cristina; Hernández, Gonzalo; Martı́nez, Marı́a José; Ochoa, Begoña

doi:10.1016/s0021-9150(00)00407-x

Cited by 51 publications

(34 citation statements)

References 55 publications

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“…This finding is notable and requires explanation. Current studies suggest that statins increase the CTSS concentration in the plasma via the statin-induced apoptosis of vascular cells 26) and/or statin-enhanced lysosomal enzyme activity in vascular cells 27) , which in turn can again induce apoptosis and CTSS extracellular leakage. However, this suggestion has limitations, as statin treatment did not change the CTSS activity in the wall of abdominal aortic aneurysms in one small case-control study 11) and CTSS deficiency by itself reduces the apoptosis of vascular macrophages 7) .…”

Section: Discussionmentioning

confidence: 99%

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Mirjanic-Azaric

Vekić

Zeljković

et al. 2014

JAT

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Aim:We hypothesized that, in stable angina patients, atorvastatin therapy lowers the cathepsin S (CTSS) concentrations, as assessed non-invasively according to a plasma analysis. In addition, the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) size and subclasses in the plasma were analysed to establish the association between CTSS and lipoprotein metabolism and determine whether this association is atorvastatin-sensitive. Methods: A total of 43 patients with stable angina received atorvastatin therapy (20 mg/day, 10 weeks). The plasma CTSS mRNA levels, CTSS protein concentrations and CTSS activity, as well as LDL and HDL size and subclasses, were analysed before and after treatment. Results: Atorvastatin treatment did not change the plasma CTSS mRNA levels, although it lowered the plasma CTSS concentrations and activity. An increased plasma CTSS concentration and activity were found to be associated with a more atherogenic LDL subclass profile (a decreased dominant LDL size and increased percentage of small, dense LDL particles). The atorvastatin-induced CTSSlowering effect was concomitant with an improvement in the LDL subclass profile, and the changes were found to be interrelated. Concomitant, interrelated changes in the CTSS levels and LDL subclass profiles were found in the LDL phenotype B patients only (a dominant LDL diameter of ≤ 25.5 nm at the start of the study). In this subgroup, lowering of the plasma CTSS mRNA level also correlated with lowering of the proportion of small, dense LDL particles. Conclusions: Atorvastatin-induced CTSS-lowering and LDL subclass profile improvements in the plasma of LDL phenotype B patients with stable angina are concomitant and interrelated. J Atheroscler Thromb, 2014; 21:868-877.

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Section: Discussionmentioning

confidence: 99%

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Mirjanic-Azaric

Vekić

Zeljković

et al. 2014

JAT

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“…The decrease in hepatic triglyceride secretion without an increase in hepatic triglyceride concentration, the reduction of hepatic FFA, and the reduction of cholesteryl ester availability derived from newly synthesized cholesterol that limits the secretion of very low density Results are expressed as means ± SD. P values for qualitative data were calculated using Fisher's exact probability test, and the P values for quantitative data were calculated using the Wilcoxon signed-rank test TNF-a tumor necrosis factor-a, FFA free fatty acid, TBARS thiobarbituric acid reactive substances, P-III-P procollagen type III propeptide, HOMA-IR homeostatic model assessment of insulin resistance, IRI immunoreactive insulin, OGTT oral glucose tolerance test, CT computerized tomography * P \ 0.05 and ** P \ 0.001, compared to the values before treatment [28,29]. Furthermore, it is reported that an animal fed a high-cholesterol diet exhibits hepatic steatosis, inflammation, ballooning, and fibrosis, histological features of NASH [30].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH

et al. 2010

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“…In our TDGA-treated mice, hepatic cholesterol levels were slightly higher but phospholipid content was not affected. It has been suggested that de novo synthesis of cholesterol (19) and phospholipid (42), rather than their concentrations, are determinants of VLDL production. Although we have no direct measurements of these parameters, in a microarray experiment employing TDGA, we found significantly reduced hepatic gene expression of Pemt, encoding phosphatidylethanolamine N-methyltransferase, a key player in phospholipid synthesis (F. R. van der Leij, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

Grefhorst¹,

Hoekstra²,

Derks³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Acute hepatic steatosis in mice by blocking ␤-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production. Am J Physiol Gastrointest Liver Physiol 289: G592-G598, 2005. First published April 7, 2005; doi:10.1152/ajpgi.00063.2005.-Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of ␤-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and PKB. Tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyl transferase-1 (CPT1), was used for this purpose. Male C57BL/6J mice received 30 mg/kg TDGA or its solvent intraperitoneally and were subsequently fasted for 12 h. CPT1 inhibition resulted in severe microvesicular hepatic steatosis (19.9 Ϯ 8.3 vs. 112.4 Ϯ 25.2 nmol TG/mg liver, control vs. treated, P Ͻ 0.05) with elevated plasma nonesterified fatty acid (0.68 Ϯ 0.25 vs. 1.21 Ϯ 0.41 mM, P Ͻ 0.05) and plasma TG (0.39 Ϯ 0.16 vs. 0.60 Ϯ 0.10 mM, P Ͻ 0.05) concentrations. VLDL-TG production rate was not affected on CPT1 inhibition (74.9 Ϯ 15.2 vs. 79.1 Ϯ 12.8 mol TG ⅐ kg Ϫ1 ⅐ min Ϫ1 , control vs. treated) although treated mice secreted larger VLDL particles (59.3 Ϯ 3.6 vs. 66.6 Ϯ 4.5 nm diameter, P Ͻ 0.05). Infusion of insulin under euglycemic conditions suppressed VLDL production rate in control and treated mice by 43 and 54%, respectively, with formation of smaller VLDL particles (51.2 Ϯ 2.5 and 53.2 Ϯ 2.8 nm diameter). Insulin-induced insulin receptor substrate (IRS)1-and IRS2-associated PI3-kinase activity and PKB-phosphorylation were not affected on TDGA treatment. In conclusion, acute hepatic steatosis caused by pharmacological inhibition of ␤-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance. tetradecylglycidic acid; triglycerides; carnitine palmitoyl transferase-1 THE LIVER IS A KEY PLAYER in the control of whole body energy metabolism by its ability to synthesize, oxidize, store, and distribute the major sources of energy, i.e., glucose and fatty acids. In fed conditions, when excess glucose is available from the intestine, plasma insulin levels are high, and glucose is stored in the liver as glycogen or enters the glycolytic pathway. High insulin suppresses hepatic glucose production (HGP), increases hepatic glucose uptake, and stimulates de novo lipogenesis (11). In addition, insulin suppresses the secretion of VLDL particles by the liver (36). The actions of insulin on the liver, initiated by binding of insulin to its receptor, involve signaling pathways that transduce its effects on gene transcription, protein metabolism, and, finally, fluxes of substrates. Of relevance for this work is insulin signaling through the phosphatidylinositol 3-kinase (PI3-kinase) pathway. On insulin binding, the insuli...

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Short- and long-term effects of atorvastatin, lovastatin and simvastatin on the cellular metabolism of cholesteryl esters and VLDL secretion in rat hepatocytes

Cited by 51 publications

References 55 publications

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Interrelated Cathepsin S-Lowering and LDL Subclass Profile Improvements Induced by Atorvastatin in the Plasma of Stable Angina Patients

Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH

Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

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