scholarly journals A three-organelle complex made by wrappER contacts with peroxisome and mitochondria responds to liver lipid flux changes

2021 ◽  
Author(s):  
Nicolò Ilacqua ◽  
Irene Anastasia ◽  
Andrea Raimondi ◽  
Philippe Lemieux ◽  
Thomas Q. de Aguiar Vallim ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Electron Tomography ◽  
Liver Lipid ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Homeostasis ◽  
Genetic Ablation ◽  
Vldl Secretion ◽  
Section Electron ◽  
Intracellular Pathways

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid (FA) in peroxisomes and mitochondria and on systemic pathways that secrete FA into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct ER compartment with apparent FA- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography, and 3D organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global FA β-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic FA flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular FA-elimination pathways in the peroxisome-wrappER-mitochondria complex.

scholarly journals The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas

1992 ◽  
Vol 284 (2) ◽  
pp. 457-462 ◽  
Author(s):  
D Wiggins ◽  
G F Gibbons
Keyword(s):  
Fatty Acids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Intracellular Pool ◽  
Hepatocyte Cultures ◽  
Vldl Secretion ◽  
Vldl Assembly ◽  
Hepatic Triacylglycerol

In hepatocyte cultures maintained in the absence of extracellular fatty acids, at least 70% of the secreted very-low-density lipoprotein (VLDL) triacylglycerol was derived via lipolysis of intracellular triacylglycerol. This proportion was unchanged when the cells were exposed for 24 h to insulin or glucagon, hormones which decreased the overall secretion of intracellular triacylglycerol, or to chloroquine or tolbutamide, agents which inhibit lysosomal lipolysis. The rate of intracellular lipolysis was 2-3-fold greater than that required to maintain the observed rate of triacylglycerol secretion. Most of the fatty acids released were returned to the intracellular pool. Neither insulin nor glucagon had any significant effect on the overall lipolysis and re-esterification of intracellular triacylglycerol. In these cases a greater proportion of the released fatty acids re-entered the cellular pool, rather than being recruited for VLDL assembly. Tolbutamide inhibited intracellular lipolysis, but suppressed VLDL secretion to a greater extent. 3,5-Dimethylpyrazole did not affect lipolysis or VLDL secretion. The increased secretion of VLDL triacylglycerol observed after exposure of cells to insulin for 3 days was not accompanied by an increased rate of intracellular lipolysis. However, a larger proportion of the triacylglycerol secreted under these conditions may not have undergone prior lipolysis.

scholarly journals Long-term maintenance of high rates of very-low-density-lipoprotein secretion in hepatocyte cultures. A model for studying the direct effects of insulin and insulin deficiency in vitro

1989 ◽  
Vol 263 (3) ◽  
pp. 937-943 ◽  
Author(s):  
J M Duerden ◽  
S M Bartlett ◽  
G F Gibbons
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Secretory Process ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Triacylglycerol Synthesis ◽  
Vldl Secretion ◽  
Pre Treatment

High rates of hepatic cellular triacylglycerol synthesis and very-low-density-lipoprotein (VLDL) triacylglycerol output were maintained in vitro for at least 3 days when hepatocytes were cultured in a medium lacking insulin but supplemented with 1 microM-dexamethasone, 10 mM-lactate, 1 mM-pyruvate and 0.75 mM-oleate (supplemented medium). Under these conditions VLDL output remained constant, whereas cell triacyglycerol content increased 10-fold over 3 days, suggesting that the secretory process was saturated. Insulin, present during the first 24 h period, enhanced the storage of cellular triacylglycerol by inhibiting the secretion of VLDL. This stored triacyglycerol was subsequently released into the medium as VLDL if insulin was removed. With the supplemented medium the increased rate of VLDL secretion after insulin removal exceeded that observed under ‘saturating’ conditions, suggesting that pre-treatment with insulin enhanced the capacity for VLDL secretion. In contrast with the short-term (24 h) effects of insulin, longer-term exposure (greater than 48 h) to insulin enhanced the secretion of VLDL compared with insulin-untreated cultures. Under these conditions, insulin increased the net rates of triacylglycerol synthesis. The results suggest that insulin affects the secretion of VLDL triacylglycerol by two distinct and opposing mechanisms: first, by direct inhibition of secretion; second by increasing triacylglycerol synthesis, which stimulates secretion. The net effect at any time depends upon the relative importance of each of these processes.

scholarly journals ChREBP Rather than SHP Regulates Hepatic VLDL Secretion

2018 ◽  
Author(s):  
Hiroyuki Niwa ◽  
Katsumi Iizuka ◽  
Takehiro Kato ◽  
Wudeluhu Wu ◽  
Hiromi Tsuchida ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Wild Type ◽  
Kinase Gene ◽  
Protein Levels ◽  
Vldl Particle ◽  
Vldl Secretion ◽  
Element Binding Protein ◽  
Rat Primary Hepatocytes

The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transactivity of each other. Mttp mRNA and protein levels of Shp/– mice were similar to those of wild-type; however, those of Chrebp–/–Shp–/– and Chrebp–/– mice were much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp–/–- mice were similar to wild-type, but were much lower in Chrebp–/– and Chrebp–/–Shp–/–- mice. These findings suggested that ChREBP rather than SHP regulates VLDL secretion and that ChREBP and SHP do not affect the transactivities of each other.

scholarly journals Effect of Long-Term Exercise on Liver Lipid Metabolism in Chinese Patients With NAFLD: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ye Gao ◽  
Jiandong Lu ◽  
Xinhong Liu ◽  
Jingqi Liu ◽  
Qirui Ma ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Meta Analysis ◽  
Liver Lipid ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Chinese Patients ◽  
Alcoholic Fatty Liver ◽  
Liver Lipid Metabolism

Purpose: Using meta-analysis to evaluate the effect of various long-term exercises (more than 4 weeks) on liver lipid metabolism of Chinese patients with non-alcoholic fatty liver disease (NAFLD) and provides more targeted exercise recommendations.Methods: Four databases consisting of PubMed, Web of Science, China Science and Technology Journal Database (VIP), China Knowledge Resource Integrated Database (CNKI) were searched up to May 2021. Randomized controlled trials (RCTs) were eligible, and the outcomes of body composition, lipid metabolism [including triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C)], and liver function [including alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] were used to assess the effectiveness of long-term exercise on Chinese patients with NAFLD.Results: Eleven articles with a total of 13 data points (involving 1,006 participants) satisfied the inclusion criteria and were pooled in the meta-analysis. The findings demonstrated that long-term exercise decreased the level of TG [−0.50, 95%CI (−0.64, −0.36)], TC [−0.55, 95%CI (−0.92, −0.18)], LDL-C [−0.29, 95%CI (−0.43, −0.15)], ALT [−3.45, 95%CI (−6.78, −0.12)], AST [−6.91, 95%CI (−10.00, −3.81)], and body mass index (BMI) of patients who did exercise last more than 6 months [−1.55, 95%CI (−2.32, −0.79)] significantly. The effect on HDL-C was not obvious.Conclusion: Long-term exercise can improve the levels of TG, TC, LDL-C, ALT, and AST in Chinese patients with NAFLD significantly, and exercise last more than 6 months can decrease the BMI of Chinese patients with NAFLD.

scholarly journals SAA1 gene polymorphisms in osteoporosis patients

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Xindie Zhou ◽  
Jin Li ◽  
Lifeng Jiang ◽  
Dong Zhou ◽  
Lidong Wu ◽  
...  
Keyword(s):  
Haplotype Analysis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Homeostasis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Amyloid A ◽  
Glucose And Lipid Homeostasis ◽  
Artery Disease ◽  
Control Study

Abstract Background: Serum amyloid A (SAA1) is an apolipoprotein that maintains glucose and lipid homeostasis. Its polymorphisms are associated with risks of myocardial infarction and coronary artery disease (CAD). Methods: However, little is known about the associations of these polymorphisms with susceptibility to osteoporosis, which we evaluated in this hospital-based case–control study involving 300 osteoporosis patients and 350 controls. Three single-nucleotide polymorphisms (SNPs) (rs183978373, rs12218, and rs10832915) were genotyped using MALDI TOF MS. Results: There were no differences in the rs183978373 and rs12218 polymorphisms between the osteoporosis group and controls. The SAA1 gene rs10832915 polymorphism increased the risk of osteoporosis in our Chinese population. The genotypes of the rs10832915 polymorphism were not significantly associated with clinical parameters (age, body mass index (BMI), high- and low-density lipoprotein (LDL), total cholesterol (TC), and T-score). Haplotype analysis revealed that the ATT haplotype had a significant correlation with a decreased risk of osteoporosis. Conclusion: In conclusion, the SAA1 rs10832915 polymorphism and its haplotypes are associated with osteoporosis, but this finding should be confirmed in large well-designed studies.

Clockmutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet

2008 ◽  
Vol 294 (1) ◽  
pp. E120-E130 ◽  
Author(s):  
Takashi Kudo ◽  
Mihoko Kawashima ◽  
Toru Tamagawa ◽  
Shigenobu Shibata
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Cholic Acid ◽  
Mouse Liver ◽  
Clock Genes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant

Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor ( Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) ( Per2) and brain and muscle arnt-like protein-1 ( Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.

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