CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis

Zhao, Lei; Zhang, Chang; Luo, Xiaoxiao; Wang, Pei; Zhou, Wei; Zhong, Sen; Xie, Yunxia; Jiang, Yibo; Yang, Ping; Tang, Renkuang; Pan, Qin; Hall, Andrew; Luong, Tu Vinh; Fan, Jian‐Gao; Varghese, Zac; Moorhead, John F.; Pinzani, Massimo; Chen, Yaxi; Ruan, Xiong Z.

doi:10.1016/j.jhep.2018.04.006

Cited by 159 publications

(155 citation statements)

References 45 publications

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“…LCFA binding to CD36 activates AMPK within minutes via its ability to dissociate Fyn from the complex as CD36 is internalized into LKB1-rich vesicles. An earlier work from our group found that CD36 translocation to the plasma membrane of hepatocytes was associated with low AMPK activity and accompanied by low hepatic fatty acid oxidation, which may also result from the increased LKB1 phosphorylation (11). These studies lead to the reasonable speculation that CD36 may be associated with autophagy through the AMPK pathway.…”

mentioning

confidence: 73%

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CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway

Li¹,

Yang²,

Zhao³

et al. 2019

Journal of Lipid Research

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104

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confidence: 73%

“…Fatty acid translocase CD36 and lipophagy 845 receptor, NF-B, and c-Jun N-terminal kinase signals to control the chronic metabolic inflammatory response (8)(9)(10)(11), confirming its significance in the pathogenesis of nonalcoholic steatohepatitis.…”

mentioning

confidence: 83%

CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway

Li¹,

Yang²,

Zhao³

et al. 2019

Journal of Lipid Research

Self Cite

104

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“…A possible node for the regulation of the metabolic switch promoted by palmitate is the interaction between adenosine monophosphate-activated protein kinase (AMPK) and CD36, which mediates palmitate entry into the cell. Palmitate interacts with CD36 and can palmitoylate it (Tao et al, 1996;Thorne et al, 2010;Zhao et al, 2018). This increases CD36 translocation to the plasma membrane and favors the formation of a complex with Fyn, Lyn and LKB1, preventing AMPK activation under chronic palmitate treatment conditions (Li et al, 2019;Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Palmitate interacts with CD36 and can palmitoylate it (Tao et al, 1996;Thorne et al, 2010;Zhao et al, 2018). This increases CD36 translocation to the plasma membrane and favors the formation of a complex with Fyn, Lyn and LKB1, preventing AMPK activation under chronic palmitate treatment conditions (Li et al, 2019;Zhao et al, 2018). Acute binding to palmitate, on the other hand, may alleviate LKB1 inhibition, activating AMPK and lipophagy (Li et al, 2019;Samovski and Abumrad, 2019;Samovski et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

Kakimoto

Zorzano

Kowaltowski

2020

Preprint

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Palmitic acid is the most abundant saturated fatty acid in human serum. In cell culture systems, palmitate overload is considered a toxic stimulus, and promotes lipid accumulation, insulin resistance, endoplasmic reticulum stress, oxidative stress, as well as cell death. An increased supply of fatty acids has also been shown to change the predominant form of the mitochondrial network, although the metabolic effects of this change are still unclear. Here, we aimed to uncover the early bioenergetic outcomes of lipotoxicity. We incubated hepatic PLC/PRF/5 cells with palmitate conjugated to BSA and followed real-time oxygen consumption and extracellular acidification for 6 hours. Palmitate increased glycolysis as soon as 1 hour after the stimulus, while oxygen consumption was not disturbed, despite overt mitochondrial fragmentation and cellular reductive imbalance.Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is not dependent on morphological changes. NAD(P)H levels were significantly abrogated in palmitate-treated cells. Knockdown of the mitochondrial NAD(P) transhydrogenase or addition of the mitochondrial oxidant-generator menadione in control cells modulated ATP production from glycolysis. Indeed, using selective inhibitors, we found that the production of superoxide/hydrogen peroxide at the IQ site of electron transport chain complex I is associated with the metabolic rewiring promoted by palmitate, while not changing mitochondrial oxygen consumption. In conclusion, we demonstrate that increased glycolytic flux linked to mitochondrially-generated redox imbalance is an early bioenergetic result of palmitate overload and lipotoxicity.

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“…It has been shown that palmitoylation of CD36 enhances fatty acid uptake activity and stabilizes its plasma membrane translocation [89]. Patients with NASH show increased CD36 palmitoylation, which causes lipid accumulation and enhanced inflammatory signaling [90]. However, the effects of CD36 palmitoylation targeting on palmitate-induced inflammation require further investigation.…”

Section: Targeting Of Palmitate-induced Pathways As a Therapeutic Strmentioning

confidence: 99%

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

Tzeng

Chyuan

Chen

2019

Cells

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Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.Fatty acid β-oxidation is a major process that provides energy by degrading fatty acids. The enzymes responsible for fatty acid β-oxidation are mainly located in the mitochondria and peroxisomes. Each β-oxidation cycle can generate one acetyl-CoA molecule, which serves as the source for tricarboxylic acid cycle progression and yields more ATP per carbon than that from sugars by oxidative phosphorylation [7]. In contrast to the removal of two carbons from long-chain fatty acids in each β-oxidation round, fatty acid synthesis is catalyzed by joining two carbon units to the growing acyl chain via the cytosolic fatty acid synthase complex [8]. Palmitate is a 16-carbon saturated fatty acid produced via the fatty acid synthesis pathway in a fatty acid synthase-dependent manner, and acts as the major lipid mediator in inflammatory response regulation. Palmitic Acid-Regulated Innate Immune ResponsesCell uptake of palmitate is mainly mediated by the membrane fatty acid transporter CD36, also known as scavenger receptor B2 [9], although palmitate can also enter cells by other mechanisms, including direct membrane interactions, albumin-mediated transfer, and lipoprotein lipase-mediated uptake [10]. Accumulating evidence suggests a critical role by palmitic acid in modulating the activation of pattern recognition receptors in innate immune cells (Figure 1). Indeed, accumulating evidence reveals that although not through direct engagement of Toll-like receptors (TLRs), palmitate can modulate TLR downstream signaling in response to their ligand stimulation [11,12]. Palmitate is believed to be a TLR4 agonist that promotes macrophage activation and lipid metabolism-associated inflammation. Recently, however, it has been demonstrated that palmitate-induced inflammatory effects are not triggered by the direct binding of palmitate to TLR4, but through a combination of palmitate-mediated and TLR4-dependent priming, which alters cellular lipid metabolic pathways, gene expression, and membrane lipid composition, the prerequisite changes that are ...

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CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis

Cited by 159 publications

References 45 publications

CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway

CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

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