Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity.

Abstract

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride-rich lipoproteins and plays a critical role in lipoprotein and free fatty acid metabolism. Genetic manipulation of LPL may be beneficial in the treatment of hypertriglyceridemias, but it is unknown whether increased LPL activity may be effective in lowering plasma cholesterol and improving insulin resistance in familial hypercholesterolemic patients. To test the hypothesis that stimulation of LPL expression may be used as an adjunctive therapy for treatment of homozygous familial hypercholesterolemia, we have generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL transgene and compared their plasma lipid levels, glucose metabolism, and body fat accumulation with those of non-Tg WHHL rabbits. Overexpression of LPL dramatically ameliorated hypertriglyceridemia in Tg WHHL rabbits. Furthermore, increased LPL activity in male Tg WHHL rabbits also corrected hypercholesterolemia (544 +/- 52 in non-Tg versus 227 +/- 29 mg/dl in Tg, p < 0.01) and reduced body fat accumulation by 61% (323 +/- 27 in non-Tg versus 125 +/- 21ginTg, p < 0.01), suggesting that LPL plays an important role in mediating plasma cholesterol homeostasis and adipose accumulation. In addition, overexpression of LPL significantly suppressed high fat diet-induced obesity and insulin resistance in Tg WHHL rabbits. These results imply that systemic elevation of LPL expression may be potentially useful for the treatment of hyperlipidemias, obesity, and insulin resistance.

• Authors: Tomonari Koike, Jingyan Liang, Xiaofei Wang, Tomonaga Ichikawa, Masashi Shiomi, George Liu, Huijun Sun, Shuji Kitajima, Masatoshi Morimoto, Teruo Watanabe, Nobuhiro Yamada, Jianglin Fan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 9 Pg. 7521-9 (Feb 27 2004) ISSN: 0021-9258 [Print] United States
• PMID: 14660566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cholesterol, HDL
• Cholesterol, LDL
• Dietary Fats
• Fatty Acids, Nonesterified
• Insulin
• Triglycerides
• Cholesterol
• Lipoprotein Lipase

Topics

• Adipose Tissue (ultrastructure)
• Animals
• Animals, Genetically Modified
• Blood Glucose (analysis)
• Blotting, Northern
• Body Composition
• Cholesterol (blood)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Dietary Fats (administration & dosage)
• Fasting
• Fatty Acids, Nonesterified (blood)
• Female
• Gene Expression
• Genetic Therapy
• Glucose Tolerance Test
• Humans
• Hyperlipidemias (enzymology, genetics, therapy)
• Insulin (blood)
• Insulin Resistance
• Lipoprotein Lipase (genetics)
• Male
• Microscopy, Electron, Scanning
• Obesity (enzymology, therapy)
• Polymerase Chain Reaction
• Rabbits
• Triglycerides (blood)