Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy

Shikuma, Cecilia; Hu, Ningjie; Milne, Cris; Yost, Fred J.; Waslien, Carol I.; Shimizu, Sheri M.; Shiramizu, Bruce

doi:10.1097/00002030-200109280-00009

Cited by 196 publications

(140 citation statements)

References 16 publications

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“…Increased systemic lactate levels were previously reported in HIV patients undergoing HAART (52). Adipose tissue mitochondrial damage from HAART with subsequent increased lactate production was hypothesized as the most likely cause of hyperlactatemia in these patients (12,45,63,67), as liver lactate clearance was found to be normal (58). Our results suggest that adipose tissue is indeed one possible source of the increased circulating lactate, but this does not preclude increased lactate production from other tissues such as muscle.…”

Section: Discussionmentioning

confidence: 59%

“…PI have been reported to induce insulin resistance, to decrease glucose transport and adipogenesis (8,48,49,57,60,70), to either increase (51) or decrease preadipocyte differentiation in 3T3-L1 adipocyte cell lines (8,14), and to increase apoptosis in human subcutaneous adipose tissue (13). In addition, NRTI have been shown to have a toxic effect on mitochondrial DNA in human subcutaneous adipose tissue (45,63,67).…”

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confidence: 99%

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Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

Johnson

Albu²,

Engelson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

125

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The lipodystrophy syndrome (adipose tissue redistribution and metabolic abnormalities) observed with highly active antiretroviral therapy (HAART) during human immunodeficiency virus (HIV) infection may be related to increased proinflammatory cytokine activity. We measured acute cytokine (TNF-α, IL-6, leptin), glycerol, and lactate secretion from abdominal subcutaneous adipose tissue (SAT), and systemic cytokine levels, in HIV-infected subjects with and without lipodystrophy (HIVL+ and HIVL–, respectively) and healthy non-HIV controls. Lipodystrophy was confirmed and characterized as adipose tissue redistribution in HIVL+ compared with HIVL– and controls, by dual-energy X-ray absorptiometry and by whole body MRI. TNF-α secretion from abdominal SAT and circulating levels of IL-6, soluble TNF receptors I and II, and insulin were elevated in HIVL+ relative to HIVL– and/or controls, particularly in HIVL+ undergoing HAART. In the HIV-infected group as a whole, IL-6 secretion from abdominal SAT and serum IL-6 were positively associated with visceral fat and were negatively associated with the relative amount of lower limb adipose tissue ( P < 0.01). Decreased leptin and increased lactate secretion from abdominal SAT were specifically associated with HAART. In conclusion, increased cytokine secretion from adipose tissue and increased systemic proinflammatory cytokine activity may play a significant role in the adipose tissue remodeling and/or the metabolic abnormalities associated with the HIV-lipodystrophy syndrome in patients undergoing HAART.

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

Johnson

Albu²,

Engelson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

125

View full text Add to dashboard Cite

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“…Lipoatrophy has been associated with decreases in mtDNA in subcutaneous fat [45]. The duration of NRTI use and the use of NRTIs with strong inhibition of mtDNA are the most important risk factors for development of lipoatrophy.…”

Section: Lipoatrophymentioning

confidence: 99%

A Review of the Toxicity of HIV Medications

et al. 2013

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Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

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“…For example, it has been shown the HAART drug combination of zidovudine (AZT) and the PI, indinavir (IDV) can disrupt the function and viability of endothelial cells due to loss of mitochondrial membrane potential; partially reversible with the thiol antioxidant N-acetylcysteine amide [32]. In adipocytes from HAART treated patients, it has also been shown that NRTI administration correlated positively with mitochondrial DNA depletion [41,42] suggesting an etiology for the lipodystrophy imparted by HAART. There are also coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to AZT, alone or in combination with the NRTI 3TC [43,44].…”

Section: Disruption Of Mitochondrial Function By Haartmentioning

confidence: 99%

Development of 2′-Deoxy-4′-C-Ethynyl-2-Fluoroadenosine (EFdA) which has Supremely High Anti-HIV Activity and Low Toxicity and Prevents the Emergence of Resistant HIV Mutants, and Discovery of Different Substrate Selectivity between Viral and Human Nucleic Acid Polymerases

Ohrui¹

2013

J Antivir Antiretrovir

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Highly Active Antiretroviral Therapy (HAART) has significantly reduced AIDS-related morbidity and mortality. However the prevalence of HIV-1-Associated Neurocognitive Disorders (HAND) has been on the rise in the post-HAART era. A majority of the side effects of HAART can in part at least be attributed directly, or indirectly, to mitochondrial dysfunction. Indeed the rapid early clinical phase-in of HAART required dose de-escalations secondary to toxicities suggested to be related to drug side effects affecting mitochondria. Central to central nervous system (CNS) function is the amyloid precursor protein (APP), the parent protein from which amyloid-beta (Aβ) peptide is generated. Aβ generation and aggregation as plaques are well known in the age related dementia, Alzheimer's disease (AD). It has been demonstrated that Aβ is common feature of the HIV infected brain as well. Further, reactive oxygen species (ROS) production is upregulated by HAART. Importantly, ROS promote β-secretase expression; a mechanism by which HAART may promote cognitive dysfunction, even in immune-competent HIV infected individuals.

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Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy

Abstract: Lipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.

Cited by 196 publications

References 16 publications

Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

A Review of the Toxicity of HIV Medications

Development of 2′-Deoxy-4′-C-Ethynyl-2-Fluoroadenosine (EFdA) which has Supremely High Anti-HIV Activity and Low Toxicity and Prevents the Emergence of Resistant HIV Mutants, and Discovery of Different Substrate Selectivity between Viral and Human Nucleic Acid Polymerases

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