Kinesin-dependent mechanism for controlling triglyceride secretion from the liver

Rai, Priyanka; Kumar, Mukesh; Sharma, G. D.; Barak, Pradeep; Kamat, Siddhesh S.; Mallik, Roop

doi:10.1073/pnas.1713292114

Cited by 44 publications

(104 citation statements)

References 42 publications

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“…Recent evidence suggests that, during the fed state, cLDs are transported toward the plus end of microtubules by kinesin-1 near the smooth ER in liver cells (29). Rai et al observed that most cLDs in rat hepatoma McA-RH7777 cells were found at the extreme periphery where the microtubule plus end exists (29). Similar observations were made with human HHL-17 hepatocytes and liver sections from fed rats.…”

Section: Synthesis and Mobilization Of Lipids For Lipoprotein Assemblymentioning

(Expert classified)

“…It is also known that cLDs interact with the ER, and thus fatty acids derived from the hydrolysis of triacylglycerols that reside in cLDs tethered to the ER can be preferentially delivered to the ER and utilized for lipid re-synthesis and lipoprotein assembly. Recent evidence suggests that, during the fed state, cLDs are transported toward the plus end of microtubules by kinesin-1 near the smooth ER in liver cells (29). Rai et al observed that most cLDs in rat hepatoma McA-RH7777 cells were found at the extreme periphery where the microtubule plus end exists (29).…”

Section: Synthesis and Mobilization Of Lipids For Lipoprotein Assemblymentioning

confidence: 99%

“…Recruitment of kinesin-1 to cLDs involves activation of the small GTPase ADP ribosylation factor 1 (ARF1) present on these cLDs (29). In the fed state, insulin signaling activates ARF-1 to ARF1-GTP, leading to recruitment of kinesin-1 to cLDs.…”

Section: Synthesis and Mobilization Of Lipids For Lipoprotein Assemblymentioning

confidence: 99%

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Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Sirwi

Hussain

2018

Journal of Lipid Research

111

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Running Title: Lipid transfer proteins and lipoprotein assemblyAbbreviations used: ARF1, ADP ribosylation factor 1; AUP1, ancient ubiquitous protein 1; Blps, apoB-containing lipoproteins; CIDEB, cell death-inducing DFF45-like effector B; COPII, coat protein complex II; cLDs, cytoplasmic lipid droplets; ER, endoplasmic reticulum; MTTP, microsomal triglyceride transfer protein; PLTP, phospholipid transfer protein AbstractA better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. ApoB-containing lipoproteins are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum and is dependent on lipid re-synthesis in the endoplasmic reticulum and on a chaperone, namely microsomal triglyceride transfer protein. Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. Microsomal triglyceride transfer protein is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of apoB-containing lipoproteins and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease. IntroductionHydrophobic lipids serve as a source of energy, structural components for membranes, and precursors of hormones. Owing to their hydrophobicity, lipids require special means of transport in the aqueous milieu of the human body. Three different modes of lipid transport are known. First, micellar solubilization of lipids in the intestinal lumen facilitates hydrolysis of dietary lipids in the lumen and uptake by enterocytes. Second, transport of lipids bound to proteins, e.g., albumin, occurs in the circulation. Third, the most efficient process of transporting lipids in bulk through an aqueous milieu of the blood circulation is via special protein-lipid macromolecular micelles called lipoproteins, which consist of a hydrophilic surface and a hydrophobic core. The hydrophilic surface is a monolayer of phospholipids that also contains free cholesterol and other exchangeable proteins called apolipoproteins. The lipoprotein core is devoid of proteins and consists of hydrophobic lipids, such as triacylglycerols, cholesteryl esters, vitamin E, and vitamin A. A major protein constituent of these lipoproteins is apoB, which is a very hydrophobic scaffolding protein. The apoB-containing lipoproteins (B-lps) are large spherical particles and are classif...

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Section: Synthesis and Mobilization Of Lipids For Lipoprotein Assemblymentioning

(Expert classified)

Section: Synthesis and Mobilization Of Lipids For Lipoprotein Assemblymentioning

confidence: 99%

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Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Sirwi

Hussain

2018

Journal of Lipid Research

111

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“…Cytosolic lipid droplets (LDs) store triglycerides (TGs) that are substrates for energy and membrane synthesis in most tissues (Murphy, 2012; Thiam and Beller, 2017). LDs are catabolized to supply fatty acid for assembling VLDL (very low density lipoprotein) particles in the smooth ER (sER) of hepatocytes (Gibbons et al, 2004; Lehner et al, 2012; Rai et al, 2017). VLDL is secreted from the liver into blood, where it is detected as serum TG.…”

Section: Introductionmentioning

confidence: 99%

Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver

Kumar

Ojha

Rai

et al. 2019

Journal of Cell Biology

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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.

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“…Recent investigations have demonstrated that both functions regulate normal hepatic physiology and when impaired contribute to the pathophysiology of liver disease. (1) The full spectrum of autophagy's metabolic functions in the liver has recently begun to be defined. The realization that insulin increases and glucagon decreases cellular levels of both autophagy and lipid breakdown led to the discovery that autophagy regulates hepatocyte lipid content and the development of hepatic steatosis.…”

Section: A Novel Mechanism Of Starvation-stimulated Hepatic Autophagymentioning

confidence: 99%

Fasting Inhibits the Recruitment of Kinesin‐1 to Lipid Droplets and Stalls Hepatic Triglyceride Secretion

Schulze

McNiven

2019

Hepatology

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Kinesin-dependent mechanism for controlling triglyceride secretion from the liver

Cited by 44 publications

References 42 publications

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Insulin activates intracellular transport of lipid droplets to release triglycerides from the liver

Fasting Inhibits the Recruitment of Kinesin‐1 to Lipid Droplets and Stalls Hepatic Triglyceride Secretion

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