Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting

Zhang, Enxiang; Cui, Wenqi; Lopresti, Michael; Mashek, Mara T.; Najt, Charles P.; Hu, Hongbo; Mashek, Douglas G.

doi:10.1194/jlr.ra119000336

Cited by 38 publications

(32 citation statements)

References 31 publications

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“…Their regulatory role was associated to an occupational function on the LDs, reducing the special availability for lipolytic enzymes ( 75 ). Hepatic PLIN5 protein synthesis and activity were both induced in mice by fasting, and signals via sirtuin-1 (SIRT1) to promote autophagy and reduce hepatic inflammatory injury under starvation ( 76 ). In addition, PLIN5 was shown to regulated the phosphorolytic state of lipolytic enzymes (ATGL, HSL, and MGL), and thereby altering their lipolytic activity ( 75 ).…”

Section: Lipophagy: the Fifth Pathway Involved In Non-alcoholic Fattymentioning

confidence: 99%

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.

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Section: Lipophagy: the Fifth Pathway Involved In Non-alcoholic Fattymentioning

confidence: 99%

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

et al. 2021

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“…PA-impaired autophagy was reactivated by PU with the reducing of LC3II/LC3I ( Figure 3A) and p62 ( Figure 3B). It is worth noting that there have been reports that in the PA-treated cell model, autophagy is also regulated by SIRT1 [35,36], which reminds us of the possibility that SIRT1 might act as a key role in PU-regulating autophagy and ER stress. The detailed mechanisms involved in the function of SIRT1-mediated autophagy under PU treatment need to be further investigated.…”

Section: Discussionmentioning

confidence: 79%

Punicalagin Inhibits Palmitate Acid-induced Lipoapoptosis through Inhibition of ER Stress, and Activation of SIRT1/Autophagy in HepG2 Cells

Zhang¹,

Wu²,

Yin³

et al. 2020

JFNR

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Lipid metabolism balance plays a vital role in maintaining normal levels of sterols, triglycerides, and free fatty acids (FFA). Inhibiting FFA-induced lipotoxicity is considered a highly potential treatment for nonalcoholic fatty liver disease (NAFLD) and other lipid metabolism diseases. Punicalagin (PU), a pomegranate-derived polyphenol, has been found to effectively regulate lipid metabolism and prevent fatty liver, cardiovascular and other chronic diseases caused by lipid metabolism disorders. In the present study, we found that PU protects HepG2 cells from palmitic acid (PA)-induced lipapoptosis. Silent information regulator 1 (SIRT1) plays a key role in protecting against lipapoptosis in HepG2 cells. Knockdown of SIRT1 significantly diminished the protective effect of PU. Besides, PU could be able to reactivate weakened autophagy and inhibit PA-induced ER stress. Our findings supported that PU can effectively attenuate FFA-induced lipotoxicity via activating SIRT1/autophagy and inhibiting ER stress.

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“…Hubert 29 et al reported that LAMP2A was required for autophagy, as it incorporated syntaxin‐17 into autophagosomes and promoted their fusion with lysosomes. Notably, Plin5 has also been found to promote macroautophagy as a means to maintain hepatocyte lipid metabolism homeostasis 30 . In view of this finding, Plin5 located in lysosomes might be not only degraded but might also be transmitting signals related to lipolysis for lysosome to induce macroautophagy by promoting the fusion of lysosomes and autophagosomes.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD

Sun

Zhang

et al. 2020

Liver International

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Background & Aims: The pathological hallmark of nonalcoholic fatty liver disease (NAFLD) is an imbalance in hepatic lipid homeostasis, in which lipophagy has been found to play a vital role. However, the underlying molecular mechanisms remain unclear. We investigated the role of chaperone-mediated autophagy (CMA) in the pathogenesis of NAFLD. Methods: CMA activity was evaluated in liver tissues from NAFLD patients and highfat diet (HFD)-fed mice. Liver-specific LAMP2A-knockout mice and HepG2 cells lacking LAMP2A [L2A(-) cells] were used to investigate the influence of CMA on lipolysis in hepatocytes. The expression of Plin5, a lipid droplet (LD)-related protein, was also evaluated in human and mouse liver tissues and in [L2A(-)] cells. Results: Here, we found disrupted CMA function in the livers of NAFLD patients and animal models, displaying obvious reduction of LAMP2A and concurrent with decreased levels of CMA-positive regulators. More LDs and higher serum triglycerides accumulated in liver-specific LAMP2A-knockout mice and L2A(-) cells under high-fat challenge. Meanwhile, deleting LAMP2A hindered LD breakdown but not increased LD formation. In addition, the LD-associated protein Plin5 is a CMA substrate, and its degradation through CMA is required for LD breakdown. Conclusions: We propose that the disruption of CMA-induced Plin5 degradation obstacles LD breakdown, explaining the lipid homeostasis imbalance in NAFLD.

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Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting

Cited by 38 publications

References 31 publications

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

Punicalagin Inhibits Palmitate Acid-induced Lipoapoptosis through Inhibition of ER Stress, and Activation of SIRT1/Autophagy in HepG2 Cells

Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD

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