Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Carotti, Simone; Aquilano, Katia; Zalfa, Francesca; Ruggiero, Sergio; Valentini, Francesco; Zingariello, Maria; Francesconi, Maria; Perrone, Giuseppe; Alletto, Francesca; Antonelli-Incalzi, Raffaele; Picardi, Antonio; Morini, Sergio; Lettieri-Barbato, Daniele; Vespasiani‐Gentilucci, Umberto

doi:10.3389/fphys.2020.00850

Cited by 89 publications

(68 citation statements)

References 44 publications

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“…The number of hepatocytes with p62 aggregation correlated positively with the number of autophagic vesicles and various NAFLD severity outcomes (including NAS, fibrosis, and serum alanine aminotransferase levels). An even more recent study confirmed this finding by immunohistochemistry staining of liver biopsies of 59 patients with steatohepatitis, In these biopsies, there was increased accumulation of p62 clusters and alterations in autophagy-related gene expression that correlated with NAS and fibrosis stage ( 66 ).…”

Section: Clinical Studiesmentioning

confidence: 69%

“…Several human association studies have demonstrated that mutations in autophagy-related genes increase the risk of NAFLD development. A recent study using both pre-clinical models and patient material demonstrated that advanced stage NAFLD is associated with greater impairments of hepatic autophagy ( 66 ) and an association was also found between the autophagy-related GTPase family M ( IRGM ) gene and increased susceptibility of NAFLD in obese children ( 84 ). In vitro experiments in HepG2 cells revealed that IRGM knockdown inhibited the autophagic flux and increased LD content while overexpression of IRGM decreased LD content, highlighting its role in lipophagy.…”

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

confidence: 99%

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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: Clinical Studiesmentioning

confidence: 69%

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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“…Autophagic degradation of LDs (lipophagy) is commonly thought necessary for TG turnover and FFA β-oxidation, which prevents lipotoxicity and further progression of the disease (Singh and Cuervo, 2011;Carotti et al, 2020). Thus, models with impaired autophagy activation are expected to accumulate more TGs in hepatocytes after an obesogenic diet, while activation of autophagy should prevent or improve this outcome.…”

Section: Nutritional Overload Modelsmentioning

confidence: 99%

“…The protective role of autophagy against steatosis development in NAFLD models is mainly associated with TG hydrolysis by lipophagy activation (Carotti et al, 2020). However, it is possible that autophagic activity may affect lipid metabolism directly or indirectly by different mechanisms.…”

Section: Further Considerationsmentioning

confidence: 99%

Autophagy in Hepatic Steatosis: A Structured Review

Ramos

Kowaltowski

Kakimoto

2021

Front. Cell Dev. Biol.

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Steatosis is the accumulation of neutral lipids in the cytoplasm. In the liver, it is associated with overeating and a sedentary lifestyle, but may also be a result of xenobiotic toxicity and genetics. Non-alcoholic fatty liver disease (NAFLD) defines an array of liver conditions varying from simple steatosis to inflammation and fibrosis. Over the last years, autophagic processes have been shown to be directly associated with the development and progression of these conditions. However, the precise role of autophagy in steatosis development is still unclear. Specifically, autophagy is necessary for the regulation of basic metabolism in hepatocytes, such as glycogenolysis and gluconeogenesis, response to insulin and glucagon signaling, and cellular responses to free amino acid contents. Also, genetic knockout models for autophagy-related proteins suggest a critical relationship between autophagy and hepatic lipid metabolism, but some results are still ambiguous. While autophagy may seem necessary to support lipid oxidation in some contexts, other evidence suggests that autophagic activity can lead to lipid accumulation instead. This structured literature review aims to critically discuss, compare, and organize results over the last 10 years regarding rodent steatosis models that measured several autophagy markers, with genetic and pharmacological interventions that may help elucidate the molecular mechanisms involved.

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“…Autophagy has been shown to be a key regulator in the control of lipid metabolism [16], and the degradation of lipids via autophagy (lipophagy) has been revealed as a key pathway for the regulation of intracellular lipid content in hepatocytes [17]. Impaired autophagy/lipophagy during aging can lead to excessive tissue lipid accumulation such as hepatic steatosis and progression of NAFLD [17][18][19]. Autophagy can be modulated by ER stress, and it has been described that impaired autophagic flux is associated with increased ER stress during NAFLD development [20].…”

Section: Introductionmentioning

confidence: 99%

Effects of Long-Term DHA Supplementation and Physical Exercise on Non-Alcoholic Fatty Liver Development in Obese Aged Female Mice

et al. 2021

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Obesity and aging are associated to non-alcoholic fatty liver disease (NAFLD) development. Here, we investigate whether long-term feeding with a docosahexaenoic acid (DHA)-enriched diet and aerobic exercise, alone or in combination, are effective in ameliorating NAFLD in aged obese mice. Two-month-old female C57BL/6J mice received control or high fat diet (HFD) for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA (15% dietary lipids replaced by a DHA-rich concentrate), DIO + EX (treadmill running), and DIO + DHA + EX up to 18 months. The DHA-rich diet reduced liver steatosis in DIO mice, decreasing lipogenic genes (Dgat2, Scd1, Srebp1c), and upregulated lipid catabolism genes (Hsl/Acox) expression. A similar pattern was observed in the DIO + EX group. The combination of DHA + exercise potentiated an increase in Cpt1a and Ppara genes, and AMPK activation, key regulators of fatty acid oxidation. Exercise, alone or in combination with DHA, significantly reversed the induction of proinflammatory genes (Mcp1, Il6, Tnfα, Tlr4) in DIO mice. DHA supplementation was effective in preventing the alterations induced by the HFD in endoplasmic reticulum stress-related genes (Ern1/Xbp1) and autophagy markers (LC3II/I ratio, p62, Atg7). In summary, long-term DHA supplementation and/or exercise could be helpful to delay NAFLD progression during aging in obesity.

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Lipophagy Impairment Is Associated With Disease Progression in NAFLD

Cited by 89 publications

References 44 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

Autophagy in Hepatic Steatosis: A Structured Review

Effects of Long-Term DHA Supplementation and Physical Exercise on Non-Alcoholic Fatty Liver Development in Obese Aged Female Mice

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