Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux

Yamamoto, Takeshi; Takabatake, Yoshitsugu; Minami, Satoshi; Sakai, Shinsuke; Fujimura, Ryuta; Takahashi, Atsushi; Namba‐Hamano, Tomoko; Matsuda, Jun; Kimura, Tomonori; Matsui, Isao; Kaimori, Jun Ya; Takeda, Hiroaki; Takahashi, Masatomo; Izumi, Yoshihiro; Bamba, Takeshi; Matsusaka, Taiji; Niimura, Fumio; Yanagita, Motoko; Isaka, Yoshitaka

doi:10.1080/15548627.2020.1782034

Cited by 57 publications

(37 citation statements)

References 44 publications

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“…5 Here, in agreement with our previous study, 34 we show PA overload reduces the autophagic flux. A similar effect of PA on autophagy has been shown on astrocytes, hepatocytes and kidney proximal tubular cells, [55][56][57] while PA has been reported to induce autophagy in cancer cell lines and cardiomyocytes, 58,59 indicating its effects on autophagy are cell type-dependent. Interestingly, we also show PA exposure affects hypothalamic neuronal function, as indicated by the decrease in the production of Pomc (Figure S1 H), as well as the reduction in insulin sensitivity.…”

Section: Discussionsupporting

confidence: 60%

Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics

Hernández-Cáceres

Cereceda

Hernández

et al. 2020

Molecular & Cellular Oncology

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High-fat diet (HFD)-induced obesity is associated with increased cancer risk. Long-term feeding with HFD increases the concentration of the saturated fatty acid palmitic acid (PA) in the hypothalamus. We previously showed that, in hypothalamic neuronal cells, exposure to PA inhibits the autophagic flux, which is the whole autophagic process from the synthesis of the autophagosomes, up to their lysosomal fusion and degradation. However, the mechanism by which PA impairs autophagy in hypothalamic neurons remains unknown. Here, we show that PA-mediated reduction of the autophagic flux is not caused by lysosomal dysfunction, as PA treatment does not impair lysosomal pH or the activity of cathepsin B.Instead, PA dysregulates autophagy by reducing autophagosome-lysosome fusion, which correlates with the swelling of endolysosomal compartments that show areduction in their dynamics. Finally, because lysosomes undergo constant dynamic regulation by the small Rab7 GTPase, we investigated the effect of PA treatment on its activity. Interestingly, we found PA treatment altered the activity of Rab7. Altogether, these results unveil the cellular process by which PA exposure impairs the autophagic flux. As impaired autophagy in hypothalamic neurons promotes obesity, and balanced autophagy is required to inhibit malignant transformation, this could affect tumor initiation, progression, and/or response to therapy of obesity-related cancers.

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Section: Discussionsupporting

confidence: 60%

Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics

Hernández-Cáceres

Cereceda

Hernández

et al. 2020

Molecular & Cellular Oncology

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“…Dysregulated autophagy can occur for multiple reasons but current scientific literature highlighted a common link in both Mets and neurological or neurodegenerative disorders. In fact, dysfunctional lysososomal acidification may be involved, leading to consequent failure of the fusion between autophagosomes and lysosomes (Yamamoto et al, 2017;Park et al, 2020;Yamamoto et al, 2020). Although this hypothesis is very fascinating, further studies are needed to confirm this link.…”

Section: Resultsmentioning

confidence: 99%

“…A further example of the effects of autophagy is confirmed by important results showing how systemic autophagic insufficiency is able to cause deterioration of adaptation to metabolic stress and facilitate progression from obesity to diabetes (Lim et al, 2014). Recently it has been shown that Mets is characterized by a dysfunctional mitophagy (Wu H. et al, 2019) and present alterations which manifest as inadequate acidification in lysosomes (Yamamoto et al, 2017;Park et al, 2020;Yamamoto et al, 2020).…”

Section: Autophagy and Metabolic Syndromementioning

confidence: 91%

From Metabolic Syndrome to Neurological Diseases: Role of Autophagy

Maiuolo

Gliozzi

Musolino

et al. 2021

Front. Cell Dev. Biol.

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Metabolic syndrome is not a single pathology, but a constellation of cardiovascular disease risk factors including: central and abdominal obesity, systemic hypertension, insulin resistance (or type 2 diabetes mellitus), and atherogenic dyslipidemia. The global incidence of Metabolic syndrome is estimated to be about one quarter of the world population; for this reason, it would be desirable to better understand the underlying mechanisms involved in order to develop treatments that can reduce or eliminate the damage caused. The effects of Metabolic syndrome are multiple and wide ranging; some of which have an impact on the central nervous system and cause neurological and neurodegenerative diseases. Autophagy is a catabolic intracellular process, essential for the recycling of cytoplasmic materials and for the degradation of damaged cellular organelle. Therefore, autophagy is primarily a cytoprotective mechanism; even if excessive cellular degradation can be detrimental. To date, it is known that systemic autophagic insufficiency is able to cause metabolic balance deterioration and facilitate the onset of metabolic syndrome. This review aims to highlight the current state of knowledge regarding the connection between metabolic syndrome and the onset of several neurological diseases related to it. Furthermore, since autophagy has been found to be of particular importance in metabolic disorders, the probable involvement of this degradative process is assumed to be responsible for the attenuation of neurological disorders resulting from metabolic syndrome.

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“…However, the STRENGTH trial reported contradictory findings, making the use of these agents uncertain with regard to cardiovascular benefits, since guideline recommendations were reported before this study [79]. Interestingly, EPA is also implicated in the prevention of palmitate-induced lipotoxicity and subsequent renal proximal tubule injury while also protects against renal fibrosis, thus halting CKD evolution [80, 81].…”

Section: Treatment Of Dyslipidemia In Ckdmentioning

confidence: 99%

Dyslipidemia in Chronic Kidney Disease: Contemporary Concepts and Future Therapeutic Perspectives

et al. 2021

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Background: Chronic kidney disease (CKD) is an increasingly prevalent disease state met with great morbidity and mortality primarily resulting from the high incidence of adverse cardiovascular outcomes. Therapeutic strategies in this patient population aim at controlling modifiable cardiovascular risk factors, including dyslipidemia. Summary: In this review article, we first provide the latest pathophysiologic evidence regarding the altered dyslipidemia pattern in CKD, followed by its contemporary management according to the latest guidelines. Moreover, we present the current progress regarding the emerging therapeutic strategies. Key Messages: The presence of renal impairment leads to alterations in cholesterol structure, metabolism, and reverse transport paired with increased oxidative stress. Statins remain the cornerstone of dyslipidemia management in patients with kidney dysfunction who are at risk for cardiovascular events. However, their efficacy is debatable in end-stage renal disease under renal replacement therapy. Therefore, novel treatment approaches aiming at hypertriglyceridemia, proprotein convertase subtilisin/kexin type 9, and lipoprotein(a) are under rigorous investigation while the research of gut microbiome might provide additional mechanistic and therapeutic insight.

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Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux

Cited by 57 publications

References 44 publications

Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics

Palmitic acid reduces the autophagic flux in hypothalamic neurons by impairing autophagosome-lysosome fusion and endolysosomal dynamics

From Metabolic Syndrome to Neurological Diseases: Role of Autophagy

Dyslipidemia in Chronic Kidney Disease: Contemporary Concepts and Future Therapeutic Perspectives

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