[39] Transcript and metabolite analysis of the effects of HIV protease inhibitors in mouse adipocytes reveals inhibition of fatty acid synthesis and a biochemical signature of energy depletion

8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

San Francisco, California - September 24 - 26, 2006

TRANSCRIPT AND METABOLITE ANALYSIS OF THE EFFECTS OF HIV PROTEASE INHIBITORS IN MOUSE ADIPOCYTES REVEALS INHIBITION OF FATTY ACID SYNTHESIS AND A BIOCHEMICAL SIGNATURE OF ENERGY DEPLETION

Antiviral Therapy 2006; 11:L26 (abstract no. 39)

OP Flint¹, C Elosua¹, RA Parker¹, CM Hamilton² and MA Noor¹
¹Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, NJ, USA; ²Metabolon Inc. Research Triangle Park, NC, USA

BACKGROUND: A combination of early metabolic and corresponding mRNA expression changes in protease inhibitor-treated adipocytes may help to identify primary cellular events in a complex process such as the development of lipoatrophy.

METHODS: We exposed 3T3-L1 adipocytes to lopinavir (LPV), indinavir (IDV), ritonavir (RTV), and atazanavir (ATV) at 30 µM and nelfinavir (NFV) at 10 µM for 16 hours. Affymetrix gene profiling was conducted and metabolites were analysed by gas or liquid chromatography mass spectrometry. Treatment comparisons were by ANOVA.

RESULTS: We found decreased saturated fatty acid content, concomitant with down regulation of expression of key lipogenic genes, key genes for oxidative glucose metabolism (TCA cycle) and decreased oxidative glucose metabolism (decreased citrate cycle intermediates and increased lactate secretion).

CONCLUSIONS: PIs differentially down-regulate fatty acid gene expression and corresponding cellular metabolite concentrations as exemplified by decreases in palmitate, an end product of de novo lipogenesis. The latter may be related to differential blockade of glucose uptake by individual PIs. We conclude that several PIs can dysregulate adipocyte lipid metabolism at a fundamental molecular level by mechanisms that could contribute to the development of clinically relevant lipoatrophy.

Table 1. (Abstract 39)
Gene‡	Description	ATV	LPV	NFV	RTV	Metabolite(s)^§

		Lipid Metabolism
ACAA1	Acetyl-Coenzyme A Acyltransferase	1.065	0.727†	0.742†	0.808†	Palmitate^*, Stearic^¶ and Palmitoleic^$ acid
ACADS	Acyl-Coenzyme A Dehydrogenase Short chain	0.924	0.452†	0.506†	0.573†
ACADM	Acetyl-Coenzyme A Dehydrogenase, Med chain	0.926	0.570†	0.663†	0.741†
ACSL1	Acyl-Coenzyme A Synthetase, Long-chain	0.726	0.205†	0.274†	0.282†
FASN	Fatty Acid Synthase	0.926	0.457†	0.492†	0.368†
ACOX2	Acyl-Coenzyme A oxidase 2	1.945†	3.584†	4.617†	7.398†
		Glucose Metabolism
LDH2	Lactate dehydrogenase	1.020	0.694†	0.723†	0.842†	Lactate^*
PCK1	Phosphoenolpyruvate carboxykinase	0.678†	0.199†	0.292†	0.268†	Malate^*/Citrate
MDH1	Malate dehydrogenase	0.825†	0.511†	0.567†	0.623†	Malate^*
SDHA	Succinate dehydrogenase	0.985	0.766†	0.754†	0.881†	Succinate/Malate^*
HK1	Hexokinase 1	1.350†	1.835†	1.73†	1.394†	Glucose^*
ACLY	ATP citrate lyase	1.248†	0.703†	0.781†	0.748†	Citrate^*

^*P<0.05. ^†P<0.001; ^‡Gene changes expressed as drug treatment/vehicle-treated control; ^§All metabolites reduced, except lactate which was increased; ^¶Direct elongation product of palmitate; ^$Δ-9 desaturase product of palmitate.

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2006-09-24
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