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

Schulze, Ryan J.; McNiven, Mark A.

doi:10.1002/hep.30104

Cited by 5 publications

(4 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that LDs purified from rat liver are transported vigorously by kinesin-1 on microtubules (Barak et al, 2013), and this transport delivers LDs to the sER inside hepatocytes, ensuring steady TG supply for VLDL production (Rai et al, 2017). The implications of these findings to liver biology were elaborated on in a commentary (Schulze and McNiven, 2019). Kinesin-1 knockdown in rat liver specifically inhibited TG secretion but had no effect on ApoB secretion, with ApoB appearing at higher density after knockdown because the secreted lipoprotein particles were TG deficient (Rai et al, 2017).…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…When mouse liver insulin expression is upregulated, kinesin-1 protein is recruited to the surface of LDs, which are subsequently transported to the surface of the smooth ER for catabolism, thereby facilitating the release of triglycerides from the liver [ 48 ]. Interestingly, fasting results in the inhibition of kinesin-1 recruitment to LDs in mouse hepatocytes, while hindering hepatic triglyceride secretion [ 49 ]. Adipose-specific Kif5b knockout mice show exacerbated diet-induced obesity and insulin resistance, suggesting that the kinesin-1 protein is associated with abnormal lipid metabolism in mouse adipocytes [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Equal distribution of lipid droplets in daughter cells is regulated by microtubules

Huang

Jin

et al. 2023

Cell Cycle

View full text Add to dashboard Cite

During eukaryotic cell division, organelles are distributed between daughter cells through a dynamic process to ensure that cells can differentiate and perform their functions correctly. Uncovering the mode of lipid droplet (LD) distribution may help reveal the mechanism of membrane remodeling during cell division and lipid droplet function. Our results showed that LDs were equally distributed in both daughter cells during cytokinesis. Further experiments demonstrated that the key factor regulating the movement of LDs is the microtubule (MT)-resident protein KIF5B. Because the KIF5B structure lacks a hydrophilic region, we believe that there are proteins that mediate the interaction between LDs and KIF5B. Mass spectrometric detection of KIF5B-interacting proteins on the surface of LDs demonstrated that LDs were first wrapped by intermediate filaments forming a meshwork and then contacted with MTs to mediate lipid droplet movement during cytokinesis. Disruption of the homogeneous distribution of LDs may hinder cell proliferation and even lead to apoptosis.

show abstract

“…LDs) could form MCS with this ERmimicking membrane (hereafter called the microsomal Supported Lipid Bilayer; mSLB). Such an assay could allow controlled in-vitro manipulation and visualization of inter-organelle contacts, also shedding light on the molecular mechanisms behind two recent discoveries:-(i) Dramatic changes in LD-ER interactions inside the liver across fed/fasted states (7,8) to facilitate systemic lipid homeostasis in a manner relevant to fatty liver disease (9), and (ii) A function for LDs in the liver as innate immune hubs to protect against bacterial infection (10). Accordingly, we modified the conventional technique (11) of preparing planar supported lipid bilayers (SLBs) by replacing synthetic liposomes with microsomal vesicles that were prepared from rat liver or from cultured cells.…”

mentioning

confidence: 99%

“…The use of this ratio (LDBOUND) therefore makes our estimate of LD-ER contact formation largely independent of variation in LD numbers across samples. We therefore expect that the quantity LDBOUND reflects changes in LD-ER binding affinity arising from changes in LD/ER membrane composition, for example in response to metabolic transitions (7)(8)(9) or immune activation (10).…”

mentioning

confidence: 99%

In-vitro Reconstitution of Membrane Contact Sites between the Endoplasmic Reticulum and Lipid Droplets

Kamerkar

Singh

Tripathy

et al. 2021

Preprint

View full text Add to dashboard Cite

Coordinated cell function requires inter-organelle communication across Membrane Contact Sites (MCS). Here we deposit ER-enriched microsomes purified from rat liver or from cultured cells on a coverslip in the form of a continuous planar membrane. We visualize real-time protein and lipid exchanges across MCS that form between this ER-mimicking membrane and lipid droplets purified from rat liver. An Optical trap is used to demonstrate physical tethering of individual lipid droplets to the ER-mimicking membrane at MCS, and to directly measure the strength of this tether. In-vitro MCS formation changes dramatically in response to metabolic state and immune activation in the animal. Surprisingly, we find that the Rab18 GTPase and Phosphatidic acid are common molecular factors to control both of these pathways. This assay could possibly be adapted to interrogate MCS formation between other membranes (e.g. mitochondria, peroxisomes, endosomes etc.), and abnormalities therein that cause neurological, metabolic and pathogenic diseases.

show abstract

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

Cited by 5 publications

References 9 publications

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

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

Equal distribution of lipid droplets in daughter cells is regulated by microtubules

In-vitro Reconstitution of Membrane Contact Sites between the Endoplasmic Reticulum and Lipid Droplets

Contact Info

Product

Resources

About