Adenovirus-mediated rescue of lipoprotein lipase-deficient mice. Lipolysis of triglyceride-rich lipoproteins is essential for high density lipoprotein maturation in mice

• Published in: The Journal of biological chemistry 2001-09, Vol.276 (39), p.36083-36090
• Main Authors: Strauss, J G, Frank, S, Kratky, D, Hämmerle, G, Hrzenjak, A, Knipping, G, von Eckardstein, A, Kostner, G M, Zechner, R
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adenovirus; Animals; Blood Glucose - metabolism; Blotting, Western; Body Weight; Cholesterol - blood; DNA, Complementary - metabolism; Fatty Acids, Nonesterified - blood; Fatty Acids, Nonesterified - metabolism; Hydrolysis; Ketones - blood; Ketones - metabolism; Lipoprotein Lipase - genetics; Lipoprotein Lipase - physiology; Lipoproteins, HDL - metabolism; Liver - metabolism; Mice; Mice, Knockout; RNA - metabolism; RNA, Messenger - metabolism; Time Factors; Triglycerides - blood; Triglycerides - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M104430200

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 5x10(9) 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 prebeta-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 prebeta-HDL and mature HDL particles supports the concept that the lipolysis of triglyceride-rich lipoproteins is an essential step for HDL maturation.