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PPAR-gamma is involved in the development of fatty liver. Deficiency of hepatic PPAR-gamma causes an impairment of triglyceride-rich lipoprotein clearance. Peroxisome proliferator-activated receptor (PPAR)-gamma plays a key role in regulating triglyceride content, blood glucose homeostasis, and insulin resistance in a steatotic diabetic mouse model, that according to a new report.
PPAR-gamma is normally expressed mainly in adipose tissue and at only very low levels in liver, the authors explain. While it is overexpressed in the liver of various murine models of diabetes or obesity, its physiological role there remains obscure.
Dr. Frank Gonzalez and colleagues from the National Institutes of Health in Bethesda, Maryland introduced a disrupted PPAR-gamma transgene into a line of obese diabetic mice with fatty livers (ob/ob mice) to investigate the effects of a liver-specific deficiency of PPAR-gamma.
Mice lacking liver-specific PPAR-gamma had dramatically improved fatty livers with significantly lower hepatic triglyceride content, the authors report, strongly suggesting that PPAR-gamma is involved in the development of fatty liver in ob/ob mice.
PPAR-gamma-deficient mice also had elevated LDL, HDL, and VLDL fractions apoB, apoE, and apoA, which suggests, the investigators write, “that the deficiency of hepatic PPAR-gamma causes an impairment of triglyceride-rich lipoprotein clearance.”
In these mice, the results indicate, deficiency of liver-specific PPAR-gamma improved liver insulin sensitivity but worsened muscle insulin sensitivity. Moreover, hyperglycemia was worse in PPAR-gamma-deficient mice.
Treatment of PPAR-gamma-deficient mice with rosiglitazone (a PPAR-gamma ligand) lowered glucose and triglyceride levels, the researchers note, and significantly improved the glucose intolerance, suggesting that these effects do not solely depend on hepatic PPAR-gamma in this model.
They concluded, “liver-specific disruption of PPAR-gamma in diabetic mice dramatically decreased hepatic triglyceride and systemically aggravated insulin resistance. However, the effect of rosiglitazone on glucose levels did not depend on hepatic PPAR-gamma.”
They add, “Results in this report and other reports suggest that adipose tissue is required for the antihyperglycemic effect of rosiglitazone.” J Clin Invest 2003;111:737-747.
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