scholarly journals Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2619
Author(s):  
Vinay Sachdev ◽  
Madalina Duta-Mare ◽  
Melanie Korbelius ◽  
Nemanja Vujić ◽  
Christina Leopold ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Metabolic Reprogramming ◽  
Whole Body ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

Lysosomal acid lipase (LAL) is the sole enzyme known to be responsible for the hydrolysis of cholesteryl esters and triglycerides at an acidic pH in lysosomes, resulting in the release of unesterified cholesterol and free fatty acids. However, the role of LAL in diet-induced adaptations is largely unexplored. In this study, we demonstrate that feeding a Western-type diet to Lal-deficient (LAL-KO) mice triggers metabolic reprogramming that modulates gut-liver cholesterol homeostasis. Induction of ileal fibroblast growth factor 15 (three-fold), absence of hepatic cholesterol 7α-hydroxylase expression, and activation of the ERK phosphorylation cascade results in altered bile acid composition, substantial changes in the gut microbiome, reduced nutrient absorption by 40%, and two-fold increased fecal lipid excretion in LAL-KO mice. These metabolic adaptations lead to impaired bile acid synthesis, lipoprotein uptake, and cholesterol absorption and ultimately to the resistance of LAL-KO mice to diet-induced obesity. Our results indicate that LAL-derived lipolytic products might be important metabolic effectors in the maintenance of whole-body lipid homeostasis.

scholarly journals Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice

2014 ◽  
Vol 307 (8) ◽  
pp. G836-G847 ◽  
Author(s):  
Amal Aqul ◽  
Adam M. Lopez ◽  
Kenneth S. Posey ◽  
Anna M. Taylor ◽  
Joyce J. Repa ◽  
...  
Keyword(s):  
Cholesterol Synthesis ◽  
Average Rate ◽  
The Body ◽  
Whole Body ◽  
Liver Cholesterol ◽  
Sterol Synthesis ◽  
Loss Of Function ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50-day-old lal −/− and matching lal +/+ mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal −/− mice sequestered cholesterol at an average rate of 3.2 mg·day−1·animal−1. The proportion of the body sterol pool contained in the liver of the lal −/− mice was 64 vs. 6.3% in their lal +/+ controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal −/− mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal −/− mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal sterol synthesis compared with their lal +/+ controls. The rate of cholesterol synthesis in the lal −/− mice exceeded that in the lal +/+ controls by 3.7 mg·day−1·animal−1. Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal −/− mice, but their rate of neutral sterol excretion was 59% higher than in their lal +/+ controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal −/− mice was 355 days.

scholarly journals Liver Bile Acid Changes in Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7451
Author(s):  
Harpreet Kaur ◽  
Drew Seeger ◽  
Svetlana Golovko ◽  
Mikhail Golovko ◽  
Colin Kelly Combs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

scholarly journals Disodium ascorbyl phytostanol phosphate (FM-VP4), a modified phytostanol, is a highly active hypocholesterolaemic agent that affects the enterohepatic circulation of both cholesterol and bile acids in mice

2009 ◽  
Vol 103 (2) ◽  
pp. 153-160 ◽  
Author(s):  
J. Méndez-González ◽  
S. Süren-Castillo ◽  
L. Calpe-Berdiel ◽  
N. Rotllan ◽  
M. Vázquez-Carrera ◽  
...  
Keyword(s):  
Bile Acid ◽  
Target Genes ◽  
Enterohepatic Circulation ◽  
Acid Output ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Farnesoid X Receptor ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism ◽  
Intestinal Cholesterol Absorption

Disodium ascorbyl phytostanol phosphate (FM-VP4) is a synthetic compound derived from sitostanol and campestanol that has proved to be efficient as a cholesterol-lowering therapy in mice and human subjects. However, the mechanism of action of FM-VP4 remains unknown. The present study tests the ability of FM-VP4 to alter intestinal and liver cholesterol homeostasis in mice. Female C57BL/6J mice were fed either a control chow or a 2 % FM-VP4-enriched diet for 4 weeks. FM-VP4 reduced the in vivo net intestinal cholesterol absorption and plasma and liver cholesterol concentrations by 2·2-, 1·5- and 1·6-fold, respectively, compared with control mice. Furthermore, FM-VP4 also showed an impact on bile acid homeostasis. In FM-VP4 mice, liver and intestinal bile acid content was increased by 1·3- and 2·3-fold, respectively, whereas faecal bile acid output was 3·3-fold lower. FM-VP4 also increased the intestinal absorption of orally administered [3H]taurocholic acid to small intestine in vivo. Inhibition of intestinal cholesterol absorption by FM-VP4 was not mediated via transcriptional increases in intestine liver X receptor (LXR)-α, adenosine triphosphate-binding cassette transporter (ABC)-A1, ABCG5/G8 nor to decreases in intestinal Niemann-Pick C1-like 1 (NPC1L1) expression. In contrast, FM-VP4 up-regulated liver LXRα, ABCA1, ABCG5, scavenger receptor class BI (SR-BI) and hydroxymethylglutaryl coenzyme A reductase (HMGCoA-R) gene expression, whereas it down-regulated several farnesoid X receptor (FXR)-target genes such as cytochrome P450 family 7 subfamily A polypeptide 1 (CYP7A1) and Na+/taurocholate co-transporter polypeptide (NTCP). In conclusion, FM-VP4 reduced intestinal cholesterol absorption, plasma and liver cholesterol and affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma cholesterol levels in normocholesterolaemic mice.

scholarly journals Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy

2020 ◽  
Author(s):  
Ada Admin ◽  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Blood Cholesterol ◽  
Autophagic Flux ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Expression Of Genes ◽  
Metabolic Role ◽  
Hypothermic Stress ◽  
Tissue Cholesterol

Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes is unclear. We show that the isolated adipocyte fraction but not the total undigested adipose tissue from obese patients has decreased LAL expression compared to non-obese. Lentiviral-mediated LAL knockdown in 3T3L1 to mimic obese adipocytes condition did not affect lysosome density or autophagic flux, but increased triglyceride storage and disrupted ER cholesterol as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than controls on a high fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol was lower than controls albeit similar triglyceridemia. Adipose-LAL overexpressing mice phenotype is dependent on the housing temperature, and develops only under mild hypothermic stress (room temperature) but not at thermoneutrality (30°C), demonstrating prominent contribution of BAT thermogenesis. LAL overexpression increased BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue cholesterol homeostasis and impacts BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.

scholarly journals Lysosomal Acid Lipase Drives Adipocyte Cholesterol Homeostasis and Modulates Lipid Storage in Obesity, Independent of Autophagy

Diabetes ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 76-90
Author(s):  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
Dominique Farabos ◽  
...  
Keyword(s):  
Lipid Storage ◽  
Cholesterol Homeostasis ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase

scholarly journals Lysosomal acid lipase drives adipocyte cholesterol homeostasis and modulates lipid storage in obesity, independent of autophagy

2020 ◽  
Author(s):  
Ada Admin ◽  
Camille Gamblin ◽  
Christine Rouault ◽  
Amélie Lacombe ◽  
Francina Langa-Vives ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Blood Cholesterol ◽  
Autophagic Flux ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Expression Of Genes ◽  
Metabolic Role ◽  
Hypothermic Stress ◽  
Tissue Cholesterol

Besides cytoplasmic lipase-dependent adipocyte fat mobilization, the metabolic role of lysosomal acid lipase (LAL), highly expressed in adipocytes is unclear. We show that the isolated adipocyte fraction but not the total undigested adipose tissue from obese patients has decreased LAL expression compared to non-obese. Lentiviral-mediated LAL knockdown in 3T3L1 to mimic obese adipocytes condition did not affect lysosome density or autophagic flux, but increased triglyceride storage and disrupted ER cholesterol as indicated by activated SREBP. Conversely, mice with adipose-specific LAL overexpression (Adpn-rtTA x TetO-hLAL) gained less weight and body fat than controls on a high fat diet, resulting in ameliorated glucose tolerance. Blood cholesterol was lower than controls albeit similar triglyceridemia. Adipose-LAL overexpressing mice phenotype is dependent on the housing temperature, and develops only under mild hypothermic stress (room temperature) but not at thermoneutrality (30°C), demonstrating prominent contribution of BAT thermogenesis. LAL overexpression increased BAT free cholesterol, decreased SREBP targets, and induced the expression of genes involved in initial steps of mitochondrial steroidogenesis, suggesting conversion of lysosome-derived cholesterol to pregnenolone. In conclusion, our study demonstrates that adipose LAL drives tissue cholesterol homeostasis and impacts BAT metabolism, suggesting beneficial LAL activation in anti-obesity approaches aimed at reactivating thermogenic energy expenditure.

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