title: In vivo structure-function studies of human hepatic lipase: the catalytic function rescues the lean phenotype of HL-deficient (hl-/-) mice.
abstract: The lean body weight phenotype of hepatic lipase (HL)-deficient mice (hl(-/-)) suggests that HL is required for normal weight gain, but the underlying mechanisms are unknown. HL plays a unique role in lipoprotein metabolism performing bridging as well as catalytic functions, either of which could participate in energy homeostasis. To determine if both the catalytic and bridging functions or the catalytic function alone are required for the effect of HL on body weight, we studied (hl(-/-)) mice that transgenically express physiologic levels of human (h)HL (with catalytic and bridging functions) or a catalytically-inactive (ci)HL variant (with bridging function only) in which the catalytic Serine 145 was mutated to Alanine. As expected, HL activity in postheparin plasma was restored to physiologic levels only in hHL-transgenic mice (hl(-/-)hHL). During high-fat diet feeding, hHL-transgenic mice exhibited increased body weight gain and body adiposity relative to hl(-/-)ciHL mice. A similar, albeit less robust effect was observed in female hHL-transgenic relative to hl(-/-)ciHL mice. To delineate the basis for this effect, we determined cumulative food intake and measured energy expenditure using calorimetry. Interestingly, in both genders, food intake was 5-10% higher in hl(-/-)hHL mice relative to hl(-/-)ciHL controls. Similarly, energy expenditure was ~10% lower in HL-transgenic mice after adjusting for differences in total body weight. Our results demonstrate that (1) the catalytic function of HL is required to rescue the lean body weight phenotype of hl(-/-) mice; (2) this effect involves complementary changes in both sides of the energy balance equation; and (3) the bridging function alone is insufficient to rescue the lean phenotype of hl(-/-)ciHL mice.
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Jeffrey
authors: J
authors: Chen
authors: Department of Dental Public Health Sciences, School of Dentistry University of Washington, Seattle, Washington.
authors: Karl J
authors: KJ
authors: Kaiyala
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Jennifer
authors: J
authors: Lam
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Nalini
authors: N
authors: Agrawal
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Lisa
authors: L
authors: Nguyen
authors: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors: Kayoko
authors: K
authors: Ogimoto
authors: Department of Pediatrics, University of Washington, Seattle, Washington.
authors: Dean
authors: D
authors: Spencer
authors: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors: Gregory J
authors: GJ
authors: Morton
authors: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors: Michael W
authors: MW
authors: Schwartz
authors: Department of Pediatrics, University of Washington, Seattle, Washington hdichek@uw.edu.
authors: Helén L
authors: HL
authors: Dichek
keywords: Catalytic function; hepatic lipase; reduced energy expenditure; weight gain