Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral‐related steatosis

Perlemuter, Gabriel; Sabile, Abdelmajid; Lettéron, Philippe; Vona, Giovanna; Topilco, André; Chrétien, Yves; Koike, Kazuhiko; Pessayre, Dominique; Chapman, John; Barba, Giovanna; Bréchot, Christian

doi:10.1096/fj.01-0396com

Cited by 542 publications

(421 citation statements)

References 49 publications

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“…6,7 Inhibition of microsomal triglyceride transfer protein also has been shown, resulting in impaired fat trafficking. 8 This finding is supported in human studies showing decreased apoB levels, a component of very low-density lipoprotein, in patients with significant hepatic steatosis. 9 Additionally, mitochondrial dysfunction and subsequent enhanced oxidative stress resulting from HCV core protein has been suggested to lead to steatosis.…”

Section: Steatosis Mediated Via Hepatitis C Virusmentioning

confidence: 67%

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Harrison

2005

Clinical Gastroenterology and Hepatology

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Section: Steatosis Mediated Via Hepatitis C Virusmentioning

confidence: 67%

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Harrison

2005

Clinical Gastroenterology and Hepatology

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“…15 Thirty minutes later, mice received a single intraperitoneal dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg or as indicated), doxycycline (0.25 mmol/kg), pirprofen (2 mmol/kg), tetracycline (0.25 mmol/kg), or tianeptine (0.5 mmol/kg) administered as a solution or a sonicated suspension in 0.2 mL of saline. Control mice received 0.2 mL of saline.…”

Section: Methodsmentioning

confidence: 99%

“…The hepatic secretion of lipoproteins was evaluated by the increase in plasma TG and Apo B after administration of Triton WR-1339 (Tyloxapol). 15 Triton WR-1339 inhibits lipoprotein lipase activity and hence blocks the peripheral removal of TG. 15,17 In 24-hour fasted animals (with no intestinal fat absorption), the Triton WR-1339 -mediated increase in plasma TG mostly reflected the hepatic secretion of TG.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in mice

2003

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Although many steatogenic drugs inhibit mitochondrial fatty acid ␤-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/ kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial ␤-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on ␤-oxidation or only MTP. (HEPATOLOGY 2003;38:133-140.)

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“…The HCV core protein has been shown to reduce the activity of microsomal triglyceride transfer protein, interfering with the assembly and secretion of very-low-density lipoprotein. 27 There is a discrepancy between these in vitro models of steatosis that have predominantly used HCV genotype 1-derived constructs and clinical studies. Steatosis is more prevalent and severe in patients infected with viral genotype 3 ( Table 1), but the explanation for this effect remains unclear.…”

Section: Steatosis Influences the Progression Of Fibrosis In Chronic Hcvmentioning

confidence: 99%

Steatosis: Co-factor in other liver diseases

2005

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The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol-and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis. (HEPATOLOGY 2005;42:5-13.)

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Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral‐related steatosis

Cited by 542 publications

References 49 publications

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in mice

Steatosis: Co-factor in other liver diseases

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