Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver

Schulze, Ryan J.; Drižytė, Kristina; Casey, Carol A.; McNiven, Mark A.

doi:10.1002/hep4.1056

Cited by 80 publications

(56 citation statements)

References 108 publications

(195 reference statements)

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“…In a highly selective form of LD-targeted autophagy, referred to as "lipophagy," the specific turnover of LDs occurs through the action of acid lipases deposited into the autolysosome (Kaur and Debnath, 2015). Lipophagy thus represents an alternative to conventional cytosolic lipase-driven LD breakdown (Weidberg et al, 2009;Singh and Cuervo, 2012;Liu and Czaja, 2013;Schulze et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes

Schott

Weller

Schulze

et al. 2019

Journal of Cell Biology

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224

155

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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.

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Section: Introductionmentioning

confidence: 99%

Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes

Schott

Weller

Schulze

et al. 2019

Journal of Cell Biology

Self Cite

224

155

View full text Add to dashboard Cite

show abstract

“…In the last years, an increasing number of studies have shown that dysregulation of lipophagy plays a pathogenetic role in the development of NAFLD, and that all the steps of this process can be affected (Patrick and Lake, 1969;Kwanten et al, 2014;Martinez-Lopez and Singh, 2015;Schulze et al, 2017). Notably, a previous study analyzed the accumulation of p62/SQTSM1 as marker of autophagy blockage in hepatocytes of NAFLD patients (Fukushima et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is associated with aging and features of metabolic syndrome. Lipotoxicity and oxidative stress are consequent to dysregulation of lipid metabolism and lipid accumulation, leading to hepatocyte injury and inflammation. Lipophagy consists in selective degradation of intracellular lipid droplets by lysosome and mounting evidence suggests that lipophagy is dysregulated in NAFLD. Here we demonstrate lipophagy impairment in experimental models of NAFLD and in a NAFLD patient cohort by histomorphological and molecular analysis. High fat diet-fed C57BL/6J male mice and high-fat/high-glucose cultured Huh7 cells showed accumulation of both p62/SQSTM1 and LC3-II protein. In 59 NAFLD patients, lipid droplet-loaded lysosomes/lipolysosomes and p62/SQSTM1 clusters correlated with NAFLD activity score (NAS) and with NAS and fibrosis stage, respectively, and levels of expression of lysosomal genes, as well as autophagy-related genes, correlated with NAS and fibrosis stage. An increased amount of lipid droplets, lipolysosomes and autophagosomes was found in subjects with NAFLD compared to healthy subjects at ultrastructural level. In conclusion, here we observed that NAFLD is characterized by histological, ultrastructural and molecular features of altered autophagy that is associated with an impaired lipid degradation. Impaired autophagy is associated with features of advanced disease. Lipopolysosomes, as individuated with light microscopy, should be further assessed as markers of disease severity in NAFLD patients.

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“…Fatty acids are mainly generated by selective autophagy of lipid droplets (lipophagy), while amino acids are generated by proteolysis through autophagy and are used for gluconeogenesis. 33,37 Therefore, autophagy plays a decisive role in regulating liver physiology and balancing liver metabolism. 38 Chronic alcohol intake or excessive energy intake causes damage to the regulation of autophagy.…”

Section: Definition Of Autophagymentioning

confidence: 99%

Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases

Kim

2020

Clin Mol Hepatol

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Alcoholic and non-alcoholic liver diseases begin from an imbalance in lipid metabolism in hepatocytes as the earliest response. Both liver diseases share common disease features and stages (i.e., steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma). However, the two diseases have differential pathogenesis and clinical symptoms. Studies have elucidated the molecular basis underlying similarities and differences in the pathogenesis of the diseases; the factors contributing to the progression of liver diseases include depletion of sulfhydryl pools, enhanced levels of reactive oxygen and nitrogen intermediates, increased sensitivity of hepatocytes to toxic cytokines, mitochondrial dysfunction, and insulin resistance. Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins and calcium depletion, contributes to the pathogenesis, often causing catastrophic cell death. Several studies have demonstrated a mechanism by which ER stress triggers liver disease progression. Autophagy is an evolutionarily conserved process that regulates organelle turnover and cellular energy balance through decomposing damaged organelles including mitochondria, misfolded proteins, and lipid droplets. Autophagy dysregulation also exacerbates liver diseases. Thus, autophagy-related molecules can be potential therapeutic targets for liver diseases. Since ER stress and autophagy are closely linked to each other, an understanding of the molecules, gene clusters, and networks engaged in these processes would be of help to find new remedies for alcoholic and non-alcoholic liver diseases. In this review, we summarize the recent findings and perspectives in the context of the molecular pathogenesis of the liver diseases.

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Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver

Cited by 80 publications

References 108 publications

Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes

Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes

Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Endoplasmic reticulum stress and autophagy dysregulation in alcoholic and non-alcoholic liver diseases

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