Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Leopold, C.
Characterization of hepatocyte-specific lysosomal acid lipase deficient mice
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 133
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- Autor*innen der Med Uni Graz:
- Leopold Christina
- Betreuer*innen:
- Fickert Peter
- Kratky Dagmar
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- Abstract:
- Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL-deficient (Lipa-/-) mice are viable but due to an abnormal lipid metabolism they exhibit growth retardation and lack white adipose tissue. Characteristically, these mice accumulate CE and TG in multiple cells and organs, especially in the liver, resulting in severe hepatomegaly and steatosis. While numerous studies have already investigated LAL deficiency in detail, it still remained elusive whether Kupffer cells or hepatocytes are primarily responsible for the observed phenotype in humans and mice. We therefore generated mice with a specific targeted deletion of LAL in hepatocytes (Liv-Lipa-/-) and studied the consequences on hepatic and systemic lipid and glucose metabolism. Liv-Lipa-/- mice fed a chow diet remained metabolically comparable to their littermate controls and only showed hepatic cholesterol crystal accumulations. When challenged with a high fat/high cholesterol diet (HF/HCD), Liv-Lipa-/- mice gained less body weight and showed a 70% reduction in white adipose tissue mass. Food intake, locomotor activity, and energy expenditure, however, remained comparable between the genotypes. Plasma lipoprotein profile analyses after FPLC separation revealed markedly increased total cholesterol concentrations in the low-density lipoprotein fraction of Liv-Lipa-/- mice. Despite a reduction in adipose tissue mass, Liv-Lipa-/- mice exhibited improved glucose clearance during both glucose and insulin tolerance tests. mRNA expression of genes involved in gluconeogenesis support the theory of improved glucose metabolism. Biochemical estimation of hepatic lipid content revealed a reduction of TG, whereas cholesterol concentrations were increased. In agreement, electron micrographs showed reduced number and size of cytosolic lipid droplets as well as cholesterol crystals in livers of Liv-Lipa-/- mice. This consequently drives liver inflammation and fibrosis. In summary, the present work provides profound evidence that Liv-Lipa-/- mice on HF/HCD mimic the phenotype observed in global Lipa-/- mice. Our observations expand the knowledge about hepatic LAL deficiency (LAL-D) and that loss of LAL in hepatocytes is responsible for increased hepatic lipid stores in LAL-D, ultimately leading to liver damage and inflammation.