Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes.

Published on Oct 7, 2019in Journal of Cell Biology10.539
路 DOI :10.1083/JCB.201803153
Micah B. Schott9
Estimated H-index: 9
(Mayo Clinic),
Shaun G. Weller15
Estimated H-index: 15
(Mayo Clinic)
+ 4 AuthorsMark A. McNiven6
Estimated H-index: 6
(Mayo Clinic)
Sources
Abstract
Lipid droplet (LD) catabolism in hepatocytes is mediated by a combination of lipolysis and a selective autophagic mechanism called lipophagy, but the relative contributions of these seemingly distinct pathways remain unclear. We find that inhibition of lipolysis, lipophagy, or both resulted in similar overall LD content but dramatic differences in LD morphology. Inhibition of the lipolysis enzyme adipose triglyceride lipase (ATGL) resulted in large cytoplasmic LDs, whereas lysosomal inhibition caused the accumulation of numerous small LDs within the cytoplasm and degradative acidic vesicles. Combined inhibition of ATGL and LAL resulted in large LDs, suggesting that lipolysis targets these LDs upstream of lipophagy. Consistent with this, ATGL was enriched in larger-sized LDs, whereas lipophagic vesicles were restricted to small LDs as revealed by immunofluorescence, electron microscopy, and Western blot of size-separated LDs. These findings provide new evidence indicating a synergistic relationship whereby lipolysis targets larger-sized LDs to produce both size-reduced and nascently synthesized small LDs that are amenable for lipophagic internalization.
Download
馃摉 Papers frequently viewed together
201517.43Hepatology
200949.96Nature
9 Authors (Rajat Singh, ..., Mark J. Czaja)
References52
Newest
#1Coline Pr茅vost (Broad Institute)H-Index: 1
#2Morris E. Sharp (U of C: University of Chicago)H-Index: 3
Last. Tobias C. WaltherH-Index: 63
view all 7 authors...
Summary Cytosolic lipid droplets (LDs) are the main storage organelles for metabolic energy in most cells. They are unusual organelles that are bounded by a phospholipid monolayer and specific surface proteins, including key enzymes of lipid and energy metabolism. Proteins targeting LDs from the cytoplasm often contain amphipathic helices, but how they bind to LDs is not well understood. Combining computer simulations with experimental studies in聽vitro and in cells, we uncover a general mechanis...
Source
#1Lin WangH-Index: 1
#2Jun Zhou (IU: Indiana University)H-Index: 2
Last. Xiao Ming Yin (IU: Indiana University)H-Index: 75
view all 6 authors...
Ethanol-induced hepatic lipophagy plays an important cytoprotective role against liver injury, but its mechanism is not fully determined. In the present study, ethanol-induced lipophagy was studied in an immortalized mouse hepatocyte line, AML12. We found that ethanol treatment elevated lipid content in these cells, which could be regulated by autophagy. To determine the potential mechanism, we investigated the role of a key adaptor molecule SQSTM1/p62. SQSTM1 can bind to LC3 on autophagosomes a...
Source
#1Rudolf Zechner (University of Graz)H-Index: 92
#2Frank Madeo (University of Graz)H-Index: 100
Last. Dagmar Kratky (Medical University of Graz)H-Index: 33
view all 3 authors...
Lipolysis degrades triacylglycerols to supply cells with free fatty acids, which are essential components of membrane lipids and substrates for energy production. Recent discoveries transformed our understanding of the functions of and crosstalk between 'neutral' lipolysis, which occurs in the cytosol, and lipophagy and 'acid' lipolysis, which occur in lysosomes, and how dysfunction in these processes contributes to metabolic diseases.
Source
#1Micah B. SchottH-Index: 9
#2Karuna Rasineni (UNMC: University of Nebraska Medical Center)H-Index: 10
Last. Mark A. McNivenH-Index: 70
view all 7 authors...
Abstract In liver steatosis i.e., fatty liver), hepatocytes accumulate many large neutral lipid-storage organelles known as lipid droplets (LDs). LDs are important in the maintenance of energy homeostasis, but the signaling mechanisms that stimulate LD metabolism in hepatocytes are poorly defined. In adipocytes, catecholamines target the 尾-adrenergic (尾-AR)/cAMP pathway to activate cytosolic lipases and induce their recruitment to the LD surface. Therefore, the goal of this study was to determin...
Source
#1Truc B. Nguyen (University of California, Berkeley)H-Index: 13
#2Sharon M. Louie (University of California, Berkeley)H-Index: 12
Last. James A. Olzmann (University of California, Berkeley)H-Index: 32
view all 8 authors...
Summary Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount of LDs increases during prolonged periods of nutrient deprivation. Why cells store FAs in LDs during an energy crisis is unknown. Our data demonstrate that mTORC1-regulated autophagy is necessary and sufficient for starvation-induced LD biogenesis. The ER-resident diacylglycerol acyltransferase 1 (DGAT1) selectively chan...
Source
#1Ryan J. SchulzeH-Index: 21
#2Kristina Dri啪yt臈 (Mayo Clinic)H-Index: 1
Last. Mark A. McNivenH-Index: 6
view all 4 authors...
The liver is a central fat-storage organ, making it especially susceptible to steatosis as well as subsequent inflammation and cirrhosis. The mechanisms by which the liver mobilizes stored lipid for energy production, however, remain incompletely defined. The catabolic process of autophagy, a well-known process of bulk cytoplasmic recycling and cellular self-regeneration, is a central regulator of lipid metabolism in the liver. In the past decade, numerous studies have examined a selective form ...
Source
#1Aishwarya Sathyanarayan (UMN: University of Minnesota)H-Index: 6
#2Mara T. Mashek (UMN: University of Minnesota)H-Index: 14
Last. Douglas G. Mashek (UMN: University of Minnesota)H-Index: 38
view all 3 authors...
Summary Hepatic lipid droplet (LD) catabolism is thought to occur via cytosolic lipases such as adipose triglyceride lipase (ATGL) or through autophagy of LDs, a process known as lipophagy. We tested the potential interplay between these metabolic processes and its effects on hepatic lipid metabolism. We show that hepatic ATGL is both necessary and sufficient to induce both autophagy and lipophagy. Moreover, lipophagy is required for ATGL to promote LD catabolism and the subsequent oxidation of ...
Source
#1Abdou Rachid Thiam (Paris Diderot University)H-Index: 21
#2Mathias Beller (HHU: University of D眉sseldorf)H-Index: 15
ABSTRACT Lipid droplets are the universal cellular organelles for the transient or long-term storage of lipids. The number, size and composition of lipid droplets vary greatly within cells in a homogenous population as well as in different cell types. The variability of intracellular lipid-storage organelles reflects the diversification of lipid droplet composition and function. Lipid droplet diversification results, for example, in two cellular lipid droplet populations that are prone to dimini...
Source
#1Shuyan Zhang (CAS: Chinese Academy of Sciences)H-Index: 14
#2Yang Wang (CAS: Chinese Academy of Sciences)H-Index: 21
Last. Pingsheng Liu (CAS: Chinese Academy of Sciences)H-Index: 51
view all 10 authors...
Lipid droplet (LD), a multi-functional organelle, is often found to associate with other cellular membranous structures and vary in size in a given cell, which may be related to their functional diversity. Here we established a method to separate LD subpopulations from isolated CHO K2 LDs into three different size categories. The subpopulation with smallest LDs was nearly free of ER and other membranous structures while those with larger LDs contained intact ER. These distinct subpopulations of ...
Source
#1Qian Peter Su (PKU: Peking University)H-Index: 12
#2Wanqing Du (THU: Tsinghua University)H-Index: 4
Last. Yujie Sun (PKU: Peking University)H-Index: 29
view all 11 authors...
Biological membrane nanotubes are tubular structures that are commonly observed within the cell and between cells. The formation and dynamics of nanotubes are increasingly recognized to play important roles in a multitude of biological progresses, such as endosomal antigen delivery in polarized T-cells1, transportation between ER and Golgi2 and between Golgi and the plasma membrane3. We recently also demonstrated the role of nanotube dynamics in autophagic lysosome reformation during autophagy4,...
Source
Cited By53
Newest
#1Mark Li (Roy J. and Lucille A. Carver College of Medicine)H-Index: 3
Source
#1Eleonora Scorletti (UPenn: University of Pennsylvania)H-Index: 19
#2Rotonya M. Carr (UW: University of Washington)
Lipid droplets (LDs) are complex and metabolically active organelles. They are composed of a neutral lipid core surrounded by a monolayer of phospholipids and proteins. LD accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a chronic, heterogeneous liver condition that can progress to liver fibrosis and hepatocellular carcinoma. Though recent research has improved our understanding of the mechanisms linking LDs accumulation to NAFL...
Source
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic m...
Source
#1Megumi IbayashiH-Index: 1
#2Ryutaro AizawaH-Index: 1
Last. Satoshi TsukamotoH-Index: 13
view all 4 authors...
Lipid droplets (LDs) consist of a core of neutral lipids such as triacylglycerols and cholesteryl esters covered by a phospholipid monolayer. Recent studies have shown that LDs not only store neutral lipids but are also associated with various physiological functions. LDs are found in most eukaryotic cells and vary in size and quantity. It has long been known that mammalian oocytes contain LDs. Porcine and bovine oocytes contain substantial amounts of LDs, which cause their cytoplasm to darken, ...
Source
#1Zizhi Dong (CQMU: Chongqing Medical University)
#2Yujia Wei (Mayo Clinic)
Last. Lili Zhang (CQMU: Chongqing Medical University)
view all 4 authors...
Nonalcoholic fatty liver disease (NAFLD) is a global health problem that develops through unclear molecular mechanisms. The P2X7 purinergic receptor (P2RX7) is an ATP-gated ion channel that belongs to the P2XR family. Thus far, studies on P2RX7 in NAFLD have been largely contradictory. Integrating experiments and modeling, we elucidate the dynamic processes of lipid droplet fusion and degradation following regulation of P2RX7. We show that activation of P2RX7 can activate the AMPK/ULK1 pathway t...
Source
#1Erdi SozenH-Index: 9
Last. Nesrin Kartal OzerH-Index: 26
view all 6 authors...
Source
#1Shin G (SKKU: Sungkyunkwan University)
#2Lee Hm (Kyung Hee University)
Last. Kyungeun Kim (SKKU: Sungkyunkwan University)H-Index: 15
view all 9 authors...
Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease that can progress to hepatic cirrhosis and cancer. Glabridin and its derivatives are potential therapeutics for some metabolic diseases. However, the therapeutic effects of glabridin and its derivatives on NASH and their biological functions are unclear. This study demonstrated the role of synthetic glabridin derivatives (SGDs) in alleviating hepatic steatosis and inflammatio...
Source
#1Min Cai (Zhejiang University of Technology)H-Index: 1
#2Ying chen (Zhejiang University of Technology)
Last. Weihong Zhong (Zhejiang University of Technology)H-Index: 11
view all 0 authors...
Abstract null null Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, ranging from benign steatosis to severe non-alcoholic steatohepatitis. Recently, it has been found that lipophagy plays a pivotal role in lipid turnover, which can alleviate NAFLD in hepatocytes. In this study, we found that a highly sulfated glucuronomannan hexamer G6S1 has the ability to enhance lipophagy. When treated with G6S1, the number and the size of lipid droplet...
Source
#1Meredith H. Wilson (CIS: Carnegie Institution for Science)H-Index: 13
#2Stephen C. Ekker (Mayo Clinic)H-Index: 62
Last. Steven A. Farber (CIS: Carnegie Institution for Science)H-Index: 32
view all 3 authors...
Cytoplasmic lipid droplets are highly dynamic storage organelles that are critical for cellular lipid homeostasis. While the molecular details of lipid droplet dynamics are a very active area of investigation, this work has been primarily performed in cultured cells. Taking advantage of the powerful transgenic and in vivo imaging opportunities available in zebrafish, we built a suite of tools to study lipid droplets in real-time from the subcellular to the whole organism level. Fluorescently tag...
Source
Lipid accumulation often leads to lipotoxic injuries to hepatocytes, which can cause nonalcoholic steatohepatitis. The association of inflammation with lipid accumulation in liver tissue has been studied for decades; however, key mechanisms have been identified only recently. In particular, it is still unknown how hepatic inflammation regulates lipid metabolism in hepatocytes. Herein, we found that PA treatment or direct stimulation of STING1 promoted, whereas STING1 deficiency impaired, MTORC1 ...
Source
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.