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Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lip...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372077/ https://www.ncbi.nlm.nih.gov/pubmed/30639734 http://dx.doi.org/10.1016/j.bbalip.2019.01.007 |
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author | Leopold, Christina Duta-Mare, Madalina Sachdev, Vinay Goeritzer, Madeleine Maresch, Lisa Katharina Kolb, Dagmar Reicher, Helga Wagner, Bettina Stojakovic, Tatjana Ruelicke, Thomas Haemmerle, Guenter Hoefler, Gerald Sattler, Wolfgang Kratky, Dagmar |
author_facet | Leopold, Christina Duta-Mare, Madalina Sachdev, Vinay Goeritzer, Madeleine Maresch, Lisa Katharina Kolb, Dagmar Reicher, Helga Wagner, Bettina Stojakovic, Tatjana Ruelicke, Thomas Haemmerle, Guenter Hoefler, Gerald Sattler, Wolfgang Kratky, Dagmar |
author_sort | Leopold, Christina |
collection | PubMed |
description | Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa(−/−)) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa(−/−) mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa(−/−) mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa(−/−) mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability. |
format | Online Article Text |
id | pubmed-6372077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-63720772019-04-01 Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation Leopold, Christina Duta-Mare, Madalina Sachdev, Vinay Goeritzer, Madeleine Maresch, Lisa Katharina Kolb, Dagmar Reicher, Helga Wagner, Bettina Stojakovic, Tatjana Ruelicke, Thomas Haemmerle, Guenter Hoefler, Gerald Sattler, Wolfgang Kratky, Dagmar Biochim Biophys Acta Mol Cell Biol Lipids Article Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa(−/−)) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa(−/−) mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa(−/−) mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa(−/−) mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability. 2019-01-09 2019-04 /pmc/articles/PMC6372077/ /pubmed/30639734 http://dx.doi.org/10.1016/j.bbalip.2019.01.007 Text en http://creativecommons.org/licenses/BY/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). |
spellingShingle | Article Leopold, Christina Duta-Mare, Madalina Sachdev, Vinay Goeritzer, Madeleine Maresch, Lisa Katharina Kolb, Dagmar Reicher, Helga Wagner, Bettina Stojakovic, Tatjana Ruelicke, Thomas Haemmerle, Guenter Hoefler, Gerald Sattler, Wolfgang Kratky, Dagmar Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title | Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title_full | Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title_fullStr | Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title_full_unstemmed | Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title_short | Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
title_sort | hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372077/ https://www.ncbi.nlm.nih.gov/pubmed/30639734 http://dx.doi.org/10.1016/j.bbalip.2019.01.007 |
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