Hepatic lipid droplet homeostasis and fatty liver disease

Seebacher, Fabian; Zeigerer, Anja; Kory, Nora; Krahmer, Natalie

doi:10.1016/j.semcdb.2020.04.011

Cited by 127 publications

(85 citation statements)

References 132 publications

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“…Furthermore, LDs have been implicated in regulating ER stress and in clearing of protein aggregates ( Walther and Farese, 2009 ; Fujimoto and Parton, 2011 ; Walther and Farese, 2012 ; Walther et al, 2017 ; Olzmann and Carvalho, 2019 ; Roberts and Olzmann, 2020 ). LD dysfunction is the hallmark of several diseases, such as obesity, diabetes, hepatic steatosis, cardiovascular disease and cancer ( Krahmer et al, 2013 ; Welte, 2015 ; Gluchowski et al, 2017 ; Goldberg et al, 2018 ; Pennetta and Welte, 2018 ; Cruz et al, 2020 ; Seebacher et al, 2020 ). Recently, motor neuron diseases have become subjects of investigation by LD experts due to aberrant LD biology observed in neurodegenerative diseases like amyotrophic lateral sclerosis, Huntington’s disease and HSP ( Farmer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Tadepalle

Rugarli

2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSPs) are genetically heterogeneous conditions caused by the progressive dying back of the longest axons in the central nervous system, the corticospinal axons. A wealth of data in the last decade has unraveled disturbances of lipid droplet (LD) biogenesis, maturation, turnover and contact sites in cellular and animal models with perturbed expression and function of HSP proteins. As ubiquitous organelles that segregate neutral lipid into a phospholipid monolayer, LDs are at the cross-road of several processes including lipid metabolism and trafficking, energy homeostasis, and stress signaling cascades. However, their role in brain cells, especially in neurons remains enigmatic. Here, we review experimental findings linking LD abnormalities to defective function of proteins encoded by HSP genes, and discuss arising questions in the context of the pathogenesis of HSP.

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Section: Introductionmentioning

confidence: 99%

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Tadepalle

Rugarli

2021

Front. Mol. Biosci.

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“…Lipid droplets are dynamic lipid-rich organelles that have been shown to function in TG and energy storage, and as a protective strategy for fatty-acid-induced lipotoxicity in the liver. However, an imbalance of lipid-droplet formation and mobilization can lead to excess lipid droplets and TG accumulation in hepatic cells, which is a pathological condition for MAFLD [73,74]. In this study, tanshinone IIA significantly ameliorated both fatty-acid-and LXRα-induced lipid-droplet accumulation in HepG2 cells.…”

Section: Discussionmentioning

confidence: 55%

Tanshinone IIA Downregulates Lipogenic Gene Expression and Attenuates Lipid Accumulation through the Modulation of LXRα/SREBP1 Pathway in HepG2 Cells

et al. 2021

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Abnormal and excessive accumulation of lipid droplets within hepatic cells is the main feature of steatosis and nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). Dysregulation of lipogenesis contributes to hepatic steatosis and plays an essential role in the pathological progress of MAFLD. Tanshinone IIA is a bioactive phytochemical isolated from Salvia miltiorrhiza Bunge and exhibits anti-inflammatory, antiatherosclerotic and antihyperlipidemic effects. In this study, we aimed to investigate the lipid-lowering effects of tanshinone IIA on the regulation of lipogenesis, lipid accumulation, and the underlying mechanisms in hepatic cells. We demonstrated that tanshinone IIA can significantly inhibit the gene expression involved in de novo lipogenesis including FASN, ACC1, and SCD1, in HepG2 and Huh 7 cells. Tanshinone IIA could increase phosphorylation of ACC1 protein in HepG2 cells. We further demonstrated that tanshinone IIA also could suppress the fatty-acid-induced lipogenesis and TG accumulation in HepG2 cells. Furthermore, tanshinone IIA markedly downregulated the mRNA and protein expression of SREBP1, an essential transcription factor regulating lipogenesis in hepatic cells. Moreover, we found that tanshinone IIA attenuated liver X receptor α (LXRα)-mediated lipogenic gene expression and lipid droplet accumulation, but did not change the levels of LXRα mRNA or protein in HepG2 cells. The molecular docking data predicted tanshinone IIA binding to the ligand-binding domain of LXRα, which may result in the attenuation of LXRα-induced transcriptional activation. Our findings support the supposition that tanshinone IIA possesses a lipid-modulating effect that suppresses lipogenesis and attenuates lipid accumulation by modulating the LXRα/SREBP1 pathway in hepatic cells. Tanshinone IIA can be potentially used as a supplement or drug for the prevention or treatment of MAFLD.

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“…Consistent with a tethering function during active lipolysis in brown adipocytes, PLIN1 co-precipitates with MFN2, and cells lacking MFN2 show reduced LDmitochondrial contacts, impaired respiratory capacity, and reduced response to adrenergic stimulation (Boutant et al, 2017). Adipose-specific MFN2 knockout mice are protected from high-fat diet-induced insulin resistance and hepatic steatosis (Seebacher et al, 2020), suggesting that LD-mitochondrial interactions affect whole-body energy homeostasis (Boutant et al, 2017). Another perilipin family member, PLIN5, also localizes at LD-mitochondrial contacts (Gemmink et al, 2018) and is upregulated in oxidative tissues (Yamaguchi et al, 2006;Vigelso et al, 2016).…”

Section: Lipid Droplets Interact With Mitochondria and Peroxisomes Lipid Droplet-mitochondrial Contactsmentioning

confidence: 66%

“…This lack of ApoB-dependent NL secretion promotes the accumulation of ApoB-free luminal LDs, which grow inside the ER lumen and eventually disintegrate the INM leading to nLD formation (Soltysik et al, 2019). Thereby, nLD formation in hepatocytes may contribute to nonalcoholic fatty liver disease and its associated complications (Seebacher et al, 2020).…”

Section: Proteins That Define Endoplasmic Reticulum-lipid Droplet Junctions Seipinmentioning

confidence: 99%

A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets

Choudhary

Schneiter

2021

Front. Cell Dev. Biol.

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Lipid droplets (LDs) constitute compartments dedicated to the storage of metabolic energy in the form of neutral lipids. LDs originate from the endoplasmic reticulum (ER) with which they maintain close contact throughout their life cycle. These ER–LD junctions facilitate the exchange of both proteins and lipids between these two compartments. In recent years, proteins that are important for the proper formation of LDs and localize to ER–LD junctions have been identified. This junction is unique as it is generally believed to invoke a transition from the ER bilayer membrane to a lipid monolayer that delineates LDs. Proper formation of this junction requires the ordered assembly of proteins and lipids at specialized ER subdomains. Without such a well-ordered assembly of LD biogenesis factors, neutral lipids are synthesized throughout the ER membrane, resulting in the formation of aberrant LDs. Such ectopically formed LDs impact ER and lipid homeostasis, resulting in different types of lipid storage diseases. In response to starvation, the ER–LD junction recruits factors that tether the vacuole to these junctions to facilitate LD degradation. In addition, LDs maintain close contacts with peroxisomes and mitochondria for metabolic channeling of the released fatty acids toward beta-oxidation. In this review, we discuss the function of different components that ensure proper functioning of LD contact sites, their role in lipogenesis and lipolysis, and their relation to lipid storage diseases.

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Hepatic lipid droplet homeostasis and fatty liver disease

Cited by 127 publications

References 132 publications

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Tanshinone IIA Downregulates Lipogenic Gene Expression and Attenuates Lipid Accumulation through the Modulation of LXRα/SREBP1 Pathway in HepG2 Cells

A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets

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