Diabetic KKAy mice exhibit increased hepatic PPARgamma1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones.
OBJECTIVE
Peroxisome proliferator-activated receptor-gamma, which is involved in the regulation of lipid homeostasis, is upregulated in the liver of obese and diabetic mice, but the biological consequences of this induction are largely unknown. This study was aimed at further characterizing this upregulation and exploring the downstream biological effects of specific activators on hepatic lipid metabolism.


METHODS
Hepatic expression of peroxisome proliferator-activated receptor-gamma1 and gamma2 mRNA and protein was analyzed by real-time polymerase chain reaction and Western immunoblotting in KKAy mice and ob/ob mice. KKAy mice were treated with thiazolidinediones, and hepatic triglyceride content and lipid distribution were analyzed biochemically and by histopathology.


RESULTS
KKAy mice exhibited a marked increase in hepatic peroxisome proliferator-activated receptor-gamma1 mRNA and protein levels, whereas the gamma2 isoform was upregulated in ob/ob mice. Treatment of KKAy mice with troglitazone or rosiglitazone resulted in severe microvesicular periacinar steatosis, whereas lean control mice did not develop any pathological liver changes. Hepatic triglyceride levels, however, were not altered by the treatment.


CONCLUSIONS
In mice with obesity-associated upregulated hepatic peroxisome proliferator-activated receptor-gamma expression, thiazolidinediones may produce hepatic steatosis. Under pathophysiological conditions, such as non-insulin-dependent diabetes, the liver may thus become sensitized towards peroxisome proliferator-activated receptor-gamma-activating drugs.
Bedoucha
M
M
Department of Non-Clinical Drug Safety, F. Hoffmann-La Roche AG, Basel, Switzerland.
Atzpodien
E
E
Boelsterli
U A
UA
D000818:Animals; D002839:Chromans / Q000009:adverse effects* / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D015870:Gene Expression; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000009:adverse effects* / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone; D015854:Up-Regulation
D002839:Chromans; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077288:Troglitazone