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J. Biol. Chem., Vol. 276, Issue 39, 36083-36090, September 28, 2001

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Adenovirus-mediated Rescue of Lipoprotein Lipase-deficient Mice
LIPOLYSIS OF TRIGLYCERIDE-RICH LIPOPROTEINS IS ESSENTIAL FOR HIGH DENSITY LIPOPROTEIN MATURATION IN MICE^*

Juliane G. Strauss, Sasa Frank^§, Dagmar Kratky, Günter Hämmerle, Andelko Hrzenjak^§, Gabriele Knipping^§, Arnold von Eckardstein^¶, Gert M. Kostner^§, and Rudolf Zechner

From the  Institute of Molecular Biology, Biochemistry, and Microbiology and ^§ Institute of Medical Biochemistry and Medical Molecular Biology, University of Graz, Graz A-8010, Austria and the ^¶ Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Münster D-48149, Germany

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides and the subsequent uptake of free fatty acids in extrahepatic tissues. Deficiency of LPL in humans (Type I hyperlipoproteinemia) is associated with massive chylomicronemia, low high density lipoprotein (HDL) cholesterol levels, and recurrent attacks of pancreatitis when not controlled by a strict diet. In contrast to humans, homozygous LPL knock-out mice (L0) do not survive suckling and die between 18 and 24 h after birth. In this study, an adenovirus-based protocol was utilized for the transient expression of LPL during the suckling period in an effort to rescue L0 mice. After a single intraperitoneal injection of 5×10⁹ plaque-forming units of LPL-expressing virus immediately after birth, more than 90% of L0 mice survived the first days of life. 3% of L0 mice survived the entire suckling period and lived for up to 20 months, although LPL activity in mouse tissues and postheparin plasma was undetectable in all animals after 6 weeks of age. Adult LPL-deficient mice were smaller than their littermates until 2-3 months of age and exhibited very high triglyceride levels in the fed (4997 ± 1102 versus 113.4 ± 18.7 mg/dl) and fasted state (2007 ± 375 versus 65.5 ± 7.4 mg/dl). Plasma total cholesterol levels, free fatty acids, and ketone bodies were elevated in L0 mice, whereas plasma glucose was normal. Most strikingly, L0 mice lacked apoA-I-containing pre-HDL particles as well as mature HDL resulting in undetectable HDL cholesterol and HDL-apoA-I levels. HDL deficiency in plasma was evident despite normal apoA-I mRNA levels in the liver and normal apoA-I protein levels in plasma, which were predominantly found in the chylomicron fraction. The absence of pre-HDL and mature HDL particles supports the concept that the lipolysis of triglyceride-rich lipoproteins is an essential step for HDL maturation.

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