High doses of stavudine induce fat wasting and mild liver damage without impairing mitochondrial respiration in mice.
OBJECTIVE
Stavudine (d4T), a nucleoside reverse-transcriptase inhibitor (NRTI), can induce lipoatrophy, fatty liver, hyperlactataemia and abnormal liver tests. NRTI toxicity is usually ascribed to mitochondrial DNA (mtDNA) depletion and impaired mitochondrial respiration. However, NRTIs could have effects unrelated to mtDNA. Recently, we reported that 100 mg/kg/day of d4T stimulated fatty acid oxidation (FAO) in mouse liver, and reduced body fatness without depleting white adipose tissue (WAT) mtDNA. We hypothesized that higher d4T doses could further reduce adiposity, while inhibiting hepatic FAO.


METHODS
Mice were treated for 2 weeks with d4T (500 mg/kg/day), L-carnitine (200 mg/kg/day) or both drugs concomitantly. Body fatness was assessed by dual energy X-ray absorptiometry, and investigations were performed in plasma, liver, muscle and WAT.


RESULTS
D4T reduced the gain of body adiposity, WAT leptin, whole body FAO and plasma ketone bodies, and increased liver triglycerides and plasma aminotransferases with mild ultrastructural abnormalities in hepatocytes. Plasma lactate and respiratory chain activities in tissues were unchanged. Stearoyl-CoA desaturase (SCD-1), an enzyme negatively regulated by leptin, was overexpressed in liver. High doses of beta-aminoisobutyric acid (BAIBA), a d4T catabolite, increased plasma ketone bodies. Although L-carnitine did not correct body adiposity, it prevented d4T-induced impairment of FAO and liver abnormalities.


CONCLUSIONS
D4T overdosage triggers fat wasting, leptin insufficiency and mild liver damage, without causing respiratory chain dysfunction. Overexpression of SCD-1 reduces fatty acid oxidation and overcomes the stimulating effect of BAIBA on hepatic FAO. L-carnitine does not correct leptin insufficiency but prevents d4T-induced impairment of FAO and liver damage.
Igoudjil
Anissa
A
INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris, France.
Abbey-Toby
Adjé
A
Begriche
Karima
K
Grodet
Alain
A
Chataigner
Karine
K
Peytavin
Gilles
G
Maachi
Mustapha
M
Colin
Marion
M
Robin
Marie-Anne
MA
Lettéron
Philippe
P
Feldmann
Gérard
G
Pessayre
Dominique
D
Fromenty
Bernard
B
D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D007657:Ketone Bodies / Q000097:blood / Q000378:metabolism; D020738:Leptin / Q000032:analysis / Q000378:metabolism; D008060:Lipodystrophy / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018119:Stavudine / Q000008:administration & dosage* / Q000009:adverse effects; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D000637:Transaminases / Q000097:blood / Q000378:metabolism; D014803:Vitamin B Complex / Q000008:administration & dosage; D019282:Wasting Syndrome / Q000139:chemically induced* / Q000378:metabolism
D000621:Aminoisobutyric Acids; D005227:Fatty Acids; D007657:Ketone Bodies; D020738:Leptin; D018894:Reverse Transcriptase Inhibitors; D014803:Vitamin B Complex; D018119:Stavudine; D013230:Stearoyl-CoA Desaturase; D000637:Transaminases; D002331:Carnitine; C033435:3-aminoisobutyric acid