Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations

Miserez, André R.; Müller, Patrick; Spaniol, Violeta

doi:10.1097/00002030-200208160-00003

Cited by 46 publications

(27 citation statements)

References 44 publications

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“…However, studies have reported an alteration in SREBP-1c expression or function in response to other PIs. Dowell et al (31) have shown that nelfinavir inhibits accumulation of mature 68-kDa SREBP-1c protein in 3T3-L1 cells, whereas indinavir induces an abnormal sequestration of SREBP-1c at the nuclear membrane (32,34) and inhibits the expression of SREBP-1c target genes (35). Finally, HIV-infected patients treated with a combination of NRTIs and PIs have a greatly reduced SREBP-1c expression in lipoatrophic superficial fat depots (37).…”

Section: Effects Of Efavirenz On Preadipocytes and Adipocytesmentioning

confidence: 99%

“…In this regard, contradictory results have been published, few studies showing a positive effect (27) and more numerous ones showing a negative effect (28 -33) of PIs on adipocyte differentiation. The inhibitory effects of PIs on adipogenesis have been related to a decreased expression in C/EBP␣ (31) or PPAR␥ (31,32) or to an altered expression or intranuclear localization of SREBP-1c (32,34,35). Interestingly, abnormal changes in SREBP-1c were also found in white adipose tissue of ritonavirtreated mice (36) and in lipoatrophic tissue from HIV-infected patients under HAART (37).…”

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confidence: 99%

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In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

Hadri

Glorian

Monsempes

et al. 2004

Journal of Biological Chemistry

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A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 M), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets. This phenomenon was rapidly reversible and was also readily detectable in the 3T3-L1 preadipose cell line and in primary cultures of human preadipocytes. When applied to mature 3T3-

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Section: Effects Of Efavirenz On Preadipocytes and Adipocytesmentioning

confidence: 99%

mentioning

confidence: 99%

In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

Hadri

Glorian

Monsempes

et al. 2004

Journal of Biological Chemistry

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“…27 Studies from cell culture and animal models have shown that PI administration may result in an increased hepatic de novo lipogenesis and cholesterol synthesis through suppression of sterol regulatory element binding protein 1 (SREBP-1). 61 Protease inhibitor treatment may also prevent apolipoprotein B degradation with an ensuring potential for increased secretion of apolipoprotein B-containing lipoproteins.…”

Section: Pathogenesis Of Antiretroviral-induced Metabolic Disordersmentioning

confidence: 99%

Human Immunodeficiency Virus and Highly Active Antiretroviral Therapy–Associated Metabolic Disorders and Risk Factors for Cardiovascular Disease

Anuurad

Semrad

Berglund

2009

Metabolic Syndrome and Related Disorders

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The successful introduction of highly active antiretroviral therapy (HAART), a combination of potent antiretroviral agents, including protease inhibitors, nucleoside reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors, has impacted positively on morbidity and mortality among human immunodefi ciency virus (HIV)-positive patients. Over time, HAART has been associated with a number of metabolic and anthropometric abnormalities, including dyslipidemia and insulin resistance as well as subcutaneous fat loss and abdominal obesity, potentially contributing to cardiovascular risk. Recent studies have more fi rmly established that both HIV infection and HAART might increase the risk of clinical cardiovascular events. Furthermore, whereas HIV/HAART is associated with multiple aspects of endocrine dysfunction, there has been less focus on bone disease, although some studies indicate a higher prevalence of osteoporosis among HIV-positive subjects compared to HIV-negative controls. The relationship between bone and fat metabolism under HIV-positive conditions deserves further attention, and available data suggest the possibility of an intriguing connection. In the future, an increasing population of aging HIV-positive patients with a spectrum of antiretroviral therapies and accumulation of endocrine abnormalities and conventional cardiovascular risk factors will present preventive and therapeutic challenges to our health-care system.

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“…89 PIs also appear to directly inhibit glucose uptake by insulin-sensitive tissue and cause the accumulation of sterol regulatory element-binding protein-1c (SREBP-1c), which is an important regulator of triglycerides, cholesterol and insulin metabolism in adiopocytes. 90 ApoC-III, an inhibitor of lipoprotein lipase, and apoEcontaining lipoproteins are increased with the use of PIs. 59 Such particles are atherogenic and have been postulated as being implicated in the HIV-associated lipodystrophy and hypertriglyceridaemia.…”

Section: Aetiology Of Human Immunodeficiency Virus-related Lipodystrophymentioning

confidence: 99%

The basis and management of metabolic abnormalities associated with cardiovascular risk in human immunodeficiency virus infection and its treatment

Crook

2007

Ann Clin Biochem

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This article was prepared at the invitation of the Clinical Sciences Review Committee of the Association for Clinical BiochemistryThe high global prevalence of human immunodeficiency virus (HIV) infection has been associated with high morbidity and mortality. The advent of highly active antiretroviral therapy (HAART) has, however, dramatically increased survival of patients infected with HIV. These patients now survive to develop metabolic complications of HIV infection and its treatment, including increased predisposition to atherosclerotic disease. HIV infection is normally associated with hypocholesterolaemia, hypertriglyceridaemia, low plasma HDL-cholesterol as well as alterations in other cardiovascular risk factors including inflammatory markers, clotting factors, homocysteine, apolipoproteins, lipoprotein (a), oxidative stress and non-esterified fatty acids. The use of HAART is, in particular, associated with dyslipidaemia and lipodystrophy with underlying insulin resistance and associated glucose intolerance. This article explores the metabolic abnormalities associated with increased cardiovascular risk that occur in HIV infection before and after antiretroviral therapy. The laboratory investigation and clinical management of HIVassociated dyslipidaemia and lipodystrophy will be discussed.

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Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations

Abstract: Indinavir inhibits important effector genes of the SREBP-1c pathway, explaining major HAART-related adverse effects.

Cited by 46 publications

References 44 publications

In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

In Vitro Suppression of the Lipogenic Pathway by the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz in 3T3 and Human Preadipocytes or Adipocytes

Human Immunodeficiency Virus and Highly Active Antiretroviral Therapy–Associated Metabolic Disorders and Risk Factors for Cardiovascular Disease

The basis and management of metabolic abnormalities associated with cardiovascular risk in human immunodeficiency virus infection and its treatment

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