triglyceride secretion
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Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1628
Author(s):  
Miriam Longo ◽  
Erika Paolini ◽  
Marica Meroni ◽  
Lorena Duca ◽  
Irene Motta ◽  
...  

Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. α-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.


Author(s):  
Miriam Longo ◽  
Erika Paolini ◽  
Marica Meroni ◽  
Lorena Duca ◽  
Irene Motta ◽  
...  

Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions in glucose metabolism, insulin resistance and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin-mimic, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid


Metabolism ◽  
2020 ◽  
Vol 103 ◽  
pp. 154029 ◽  
Author(s):  
Yang Li ◽  
Mingyuan Tian ◽  
Mengliu Yang ◽  
Gangyi Yang ◽  
Jianrong Chen ◽  
...  

2019 ◽  
Vol 218 (11) ◽  
pp. 3697-3713 ◽  
Author(s):  
Mukesh Kumar ◽  
Srikant Ojha ◽  
Priyanka Rai ◽  
Alaumy Joshi ◽  
Siddhesh S. Kamat ◽  
...  

Triglyceride-rich lipid droplets (LDs) are catabolized with high efficiency in hepatocytes to supply fatty acids for producing lipoprotein particles. Fasting causes a massive influx of adipose-derived fatty acids into the liver. The liver in the fasted state is therefore bloated with LDs but, remarkably, still continues to secrete triglycerides at a constant rate. Here we show that insulin signaling elevates phosphatidic acid (PA) dramatically on LDs in the fed state. PA then signals to recruit kinesin-1 motors, which transport LDs to the peripherally located smooth ER inside hepatocytes, where LDs are catabolized to produce lipoproteins. This pathway is down-regulated homeostatically when fasting causes insulin levels to drop, thus preventing dangerous elevation of triglycerides in the blood. Further, we show that a specific peptide against kinesin-1 blocks triglyceride secretion without any apparent deleterious effects on cells. Our work therefore reveals fundamental mechanisms that maintain lipid homeostasis across metabolic states and leverages this knowledge to propose a molecular target against hyperlipidemia.


2019 ◽  
Vol 104 (12) ◽  
pp. 6171-6181 ◽  
Author(s):  
Kelli A Lytle ◽  
Nikki C Bush ◽  
Jessica M Triay ◽  
Todd A Kellogg ◽  
Michael L Kendrick ◽  
...  

Abstract Objective Nonalcoholic fatty liver disease can lead to hepatic inflammation/damage. Understanding the physiological mechanisms that contribute to excess hepatic lipid accumulation may help identify effective treatments. Design We recruited 25 nondiabetic patients with severe obesity scheduled for bariatric surgery. To evaluate liver export of triglyceride fatty acids, we measured very-low-density lipoprotein (VLDL)–triglyceride secretion rates the day prior to surgery using an infusion of autologous [1-14C]triolein-labeled VLDL particles. Ketone body response to fasting and intrahepatic long-chain acylcarnitine concentrations were used as indices of hepatic fatty acid oxidation. We measured intraoperative hepatic uptake rates of plasma free fatty acids using a continuous infusion of [U-13C]palmitate, combined with a bolus dose of [9,10-3H]palmitate and carefully timed liver biopsies. Total intrahepatic lipids were measured in liver biopsy samples to determine fatty liver status. The hepatic concentrations and enrichment from [U-13C]palmitate in diacylglycerols, sphingolipids, and acyl-carnitines were measured using liquid chromatography/tandem mass spectrometry. Results Among study participants with fatty liver disease, intrahepatic lipid was negatively correlated with VLDL-triglyceride secretion rates (r = −0.92, P = 0.01) but unrelated to hepatic free fatty acid uptake or indices of hepatic fatty acid oxidation. VLDL-triglyceride secretion rates were positively correlated with hepatic concentrations of saturated diacylglycerol (r = 0.46, P = 0.02) and sphingosine-1-phosphate (r = 0.44, P = 0.03). Conclusion We conclude that in nondiabetic humans with severe obesity, excess intrahepatic lipid is associated with limited export of triglyceride in VLDL particles rather than increased uptake of systemic free fatty acids.


2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Martina Theresa Hackl ◽  
Clemens Fürnsinn ◽  
Christina Maria Schuh ◽  
Martin Krssak ◽  
Fabrizia Carli ◽  
...  

2018 ◽  
Vol 391 (10) ◽  
pp. 1075-1083 ◽  
Author(s):  
Kumiko Taguchi ◽  
Nanami Bessho ◽  
Mari Hida ◽  
Haruka Narimatsu ◽  
Takayuki Matsumoto ◽  
...  

2018 ◽  
Vol 35 (7) ◽  
pp. 885-895 ◽  
Author(s):  
Yan Su ◽  
Ewout Foppen ◽  
Frederico Sander Mansur Machado ◽  
Eric Fliers ◽  
Andries Kalsbeek

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