Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells

Funatsu, Toshiyuki; Suzuki, Keiko; Goto, Masahiko; Arai, Yukinori; Kakuta, Hirotoshi; Tanaka, Hideyuki; Yasuda, Shinichi; Ida, Motoko; Nishijima, Satomi; Miyata, Keiji

doi:10.1016/s0021-9150(00)00714-0

Cited by 48 publications

(34 citation statements)

References 45 publications

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“…The reduced efficacy of statins in rodents compared with humans has been explained by the fact that statins primarily control levels of LDL cholesterol, which is compared with HDL a minor component in plasma lipoproteins of mice (47). The inhibition of cholesterol synthesis by statins has been described in numerous cell culture studies (19,48). Assuming that this effect can be translated to in vivo conditions, cholesterol synthesis is rarely measured in experiments in humans or rodent models.…”

Section: Discussionmentioning

confidence: 99%

“…After 5 days of statin treatment, mice were injected intravenously with D 5 -cholesterol and orally gavaged with D 7 -cholesterol; blood spots were taken from the tail vein at 0, 3,6,12,24,48,72,92,120,144,168, and 192 h after administration of the stably labeled isotopes, to measure the absorption of cholesterol (31). To assess cholesterol synthesis, 2% to the samples.…”

Section: Methodsmentioning

confidence: 99%

“…points 0, 24,31,48,55, and 72 h. Feces were collected during 24 h prior to termination. At the end of the experiment, bile cannulations were performed, and bile was collected continuously for 30 min as described by Brufau and Groen (31).…”

mentioning

confidence: 99%

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Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

Schonewille

Boer

Mele

et al. 2016

Journal of Lipid Research

117

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

Schonewille

Boer

Mele

et al. 2016

Journal of Lipid Research

117

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“…Animal and cell culture studies have shown either no effect (19)(20)(21) or an increase (19,22,23) in hepatic TG synthesis induced by statin therapy. In previous work validating our techniques, Patterson et al (13) showed that the monoexponential slope and the model-derived FCR (which accounts for hepatic TG turnover) are essentially equal when the turnover rate is ,0.4 pools/h, which was the case in all but one of our studies.…”

Section: Discussionmentioning

confidence: 99%

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Isley

Miles

Patterson

et al. 2006

Journal of Lipid Research

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Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 6 4.9 vs. 24.4 6 1.9 mmol/min; P , 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 6 0.03 vs. 0.16 6 0.02 pools/h; P , 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P , 0.03) and a 21% increase in postheparin LPL activity (P , 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. HMG-CoA reductase inhibitors, or statins, are widely used in diabetic patients and have been shown to decrease cardiovascular morbidity in individuals with type 2 diabetes (5, 6). The major effect of statins is a reduction in low density lipoprotein-cholesterol (LDL-C) concentrations, primarily mediated by inhibition of the rate-limiting step in cholesterol biosynthesis, resulting in an increase in LDL receptors in the liver (7). In addition, statins can reduce TGs and increase HDL-C (8, 9), all of which lead to a reduced risk for coronary heart disease (CHD) in patients with type 2 diabetes mellitus (5, 6, 10).The mechanism responsible for the TG-lowering effect of statins is poorly defined. In theory, it could be related to decreased VLDL production (presumably secondary to decreased availability of hepatic free cholesterol for particle assembly), increased clearance of VLDL through the LDL receptor (or other lipoprotein receptors), increased delipidation of VLDL particles via LPL, or a combination of these mechanisms. To address these questions, we determined triglyceride-rich lipoprotein triglyceride (TRL-TG, which is predominantly VLDL) production and clearance in subjects with type 2 diabetes mellitus and hypertriglyceridemia on placebo and high-dose simvastatin therapy (80 mg daily) for 12 weeks and in nondiabetic controls. RESEARCH DESIGN AND METHODS Study subjects

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“…Caco-2 cells (passages [35][36][37][38][39][40][41][42][43][44][45], used for transfection experiments, were cultured in a controlled environment (37°C, 5% CO 2 ) in Dulbecco's modified Eagle's medium, 4 mM glutamine, 1% non-essential amino acids, 100 units/ml penicillin, 100 g/ml streptomycin supplemented with 20% FCS. Medium was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

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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Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells

Cited by 48 publications

References 45 publications

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

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

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