Breaking fat: The regulation and mechanisms of lipophagy

Schulze, Ryan J.; Sathyanarayan, Aishwarya; Mashek, Douglas G.

doi:10.1016/j.bbalip.2017.06.008

Cited by 189 publications

(130 citation statements)

References 130 publications

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“…It is now recognized that LD catabolism in hepatocytes is also regulated by degradation through autophagic mechanisms (lipophagy), which recently has been mechanistically linked to ATGL . We found that cyclin D1 inhibited autophagy in hepatic cells, as has been shown in other cell types .…”

Section: Discussionsupporting

confidence: 75%

“…We next examined proteins involved in lipolysis in hepatocytes. The initial step in cytoplasmic LD lipolysis is catalyzed by ATGL, which is recruited to the surface of LDs . The factors regulating hepatic ATGL activity are incompletely characterized, but this lipase is activated by binding to comparative gene identification‐58 (CGI‐58; gene name, Abdh5 ) and inhibited by G0S2 .…”

Section: Resultsmentioning

confidence: 99%

“…An emerging body of literature has highlighted the importance of lipophagy, which uses autophagy mediators to promote lipolysis in the lysosomes and had been considered to be distinct from ATGL‐mediated lipolysis in the cytoplasm . However, newer studies have shown significant crosstalk between these two processes and that they are functionally linked . For example, a recent paper demonstrated that ATGL triggers lipophagy in hepatocytes and that autophagy regulators are required for ATGL‐mediated lipolysis, indicating that the two processes are interconnected .…”

Section: Resultsmentioning

confidence: 99%

“…Cyclin D1 regulated the mRNA of each of these genes (in a pattern that would predict decreased lipolysis), but we did not observe a similar change in the expression of their respective proteins. The regulation of ATGL activity, which catalyzes a key initial step in cytoplasmic lipolysis, is complex and incompletely understood but appears to involve several factors, including phosphorylation, binding to associated regulator proteins, and intracellular trafficking . Further study will be required to determine whether cyclin D1 regulates ATGL activity through one of these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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During normal proliferation, hepatocytes accumulate triglycerides (TGs) in lipid droplets (LDs), but the underlying mechanisms and functional significance of this steatosis are unknown. In the current study, we examined the coordinated regulation of cell cycle progression and LD accumulation. As previously shown, hepatocytes develop increased LD content after mitogen stimulation. Cyclin D1, in addition to regulating proliferation, was both necessary and sufficient to promote LD accumulation in response to mitogens. Interestingly, cyclin D1 promotes LD accumulation by inhibiting the breakdown of TGs by lipolysis through a mechanism involving decreased lipophagy, the autophagic degradation of LDs. To examine whether inhibition of lipolysis is important for cell cycle progression, we overexpressed adipose TG lipase (ATGL), a key enzyme involved in TG breakdown. As expected, ATGL reduced LD content but also markedly inhibited hepatocyte proliferation, suggesting that lipolysis regulates a previously uncharacterized cell cycle checkpoint. Consistent with this, in mitogen‐stimulated cells with small interfering RNA‐mediated depletion of cyclin D1 (which inhibits proliferation and stimulates lipolysis), concurrent ATGL knockdown restored progression into S phase. Following partial hepatectomy, a model of robust hepatocyte proliferation in vivo, ATGL overexpression led to decreased LD content, cell cycle inhibition, and marked liver injury, further indicating that down‐regulation of lipolysis is important for normal hepatocyte proliferation. Conclusion: We suggest a new relationship between steatosis and proliferation in hepatocytes: cyclin D1 inhibits lipolysis, resulting in LD accumulation, and suppression of lipolysis is necessary for cell cycle progression.

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Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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“…Since PLIN1 and PLIN2 are targets for UPS degradation, it is possible that the UPS regulates LD function through effects on macrolipophagy. For a more extensive recent review of macrolipophagy see Schulze et al (34). …”

Section: Lipophagy: Ld Autophagymentioning

confidence: 99%

Lipid droplet autophagy during energy mobilization lipid homeostasis and protein quality control

2018

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Lipid droplets (LDs) have well-established functions as sites for lipid storage and energy mobilization to meet the metabolic demands of cells. However, recent studies have expanded the roles of LDs to protein quality control. Lipophagy, or LD degradation by autophagy, plays a vital role not only in the mobilization of free fatty acids (FFAs) and lipid homeostasis at LDs, but also in the adaptation of cells to certain forms of stress including lipid imbalance. Recent studies have provided new mechanistic insights about the diverse types of lipophagy, in particular microlipophagy. This review summarizes key findings about the mechanisms and functions of lipophagy and highlights a novel function of LD microlipophagy as a mechanism to maintain endoplasmic reticulum (ER) proteostasis under conditions of lipid imbalance.

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