Key points are not available for this paper at this time.
Fatty acid translocase cluster of differentiation (CD36) is a multifunctional membrane protein that facilitates the uptake of long-chain fatty acids. Lipophagy is autophagic degradation of lipid droplets. Accumulating evidence suggests that CD36 is involved in the regulation of intracellular signal transduction that modulates fatty acid storage or usage. However, little is known about the relationship between CD36 and lipophagy. In this study, we found that increased CD36 expression was coupled with decreased autophagy in the livers of mice treated with a high-fat diet. Overexpressing CD36 in HepG2 and Huh7 cells inhibited autophagy, while knocking down CD36 expression induced autophagy due to the increased autophagosome formation in autophagic flux. Meanwhile, knockout of CD36 in mice increased autophagy, while the reconstruction of CD36 expression in CD36-knockout mice reduced autophagy. CD36 knockdown in HepG2 cells increased lipophagy and β-oxidation, which contributed to improving lipid accumulation. In addition, CD36 expression regulated autophagy through the AMPK pathway, with phosphorylation of ULK1/Beclin1 also involved in the process. These findings suggest that CD36 is a negative regulator of autophagy, and the induction of lipophagy by ameliorating CD36 expression can be a potential therapeutic strategy for the treatment of fatty liver diseases through attenuating lipid overaccumulation. Fatty acid translocase cluster of differentiation (CD36) is a multifunctional membrane protein that facilitates the uptake of long-chain fatty acids. Lipophagy is autophagic degradation of lipid droplets. Accumulating evidence suggests that CD36 is involved in the regulation of intracellular signal transduction that modulates fatty acid storage or usage. However, little is known about the relationship between CD36 and lipophagy. In this study, we found that increased CD36 expression was coupled with decreased autophagy in the livers of mice treated with a high-fat diet. Overexpressing CD36 in HepG2 and Huh7 cells inhibited autophagy, while knocking down CD36 expression induced autophagy due to the increased autophagosome formation in autophagic flux. Meanwhile, knockout of CD36 in mice increased autophagy, while the reconstruction of CD36 expression in CD36-knockout mice reduced autophagy. CD36 knockdown in HepG2 cells increased lipophagy and β-oxidation, which contributed to improving lipid accumulation. In addition, CD36 expression regulated autophagy through the AMPK pathway, with phosphorylation of ULK1/Beclin1 also involved in the process. These findings suggest that CD36 is a negative regulator of autophagy, and the induction of lipophagy by ameliorating CD36 expression can be a potential therapeutic strategy for the treatment of fatty liver diseases through attenuating lipid overaccumulation. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, with prevalence estimates ranging from 25% to 45% (1Rinella M.E. Nonalcoholic fatty liver disease: a systematic review.JAMA. 2015; 313: 2263-2273Crossref PubMed Scopus (1480) Google Scholar). NAFLD is considered to be the liver manifestation of metabolic syndrome, which encompasses a wide spectrum beginning with steatosis (2Shen J. Chan H.L. Wong G.L. Choi P.C. Chan A.W. Chan H.Y. Chim A.M. Yeung D.K. Chan F.K. Woo J. et al.Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.J. Hepatol. 2012; 56: 1363-1370Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 3Pais R. Charlotte F. Fedchuk L. Bedossa P. Lebray P. Poynard T. Ratziu V. Group L.S. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver.J. Hepatol. 2013; 59: 550-556Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). The cluster of differentiation 36 (CD36) belongs to the scavenger receptor family, also known as fatty acid translocase, that facilitates the uptake of long-chain fatty acids (LCFAs) and is widely expressed on the surface of many cell types in vertebrates (4Hoosdally S.J. Andress E.J. Wooding C. Martin C.A. Linton K.J. The human scavenger receptor CD36: glycosylation status and its role in trafficking and function.J. Biol. Chem. 2009; 284: 16277-16288Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 5Zhong S. Zhao L. Wang Y. Zhang C. Liu J. Wang P. Zhou W. Yang P. Varghese Z. Moorhead J.F. et al.Cluster of differentiation 36 deficiency aggravates macrophage infiltration and hepatic inflammation by upregulating monocyte chemotactic protein-1 expression of hepatocytes through histone deacetylase 2-dependent pathway.Antioxid. Redox Signal. 2017; 27: 201-214Crossref PubMed Scopus (25) Google Scholar). CD36 recognizes different ligands and may promote different intracellular signaling pathways. This multifunctional membrane glycoprotein has been studied extensively in relation to its role in the uptake of LCFAs, which are involved in NAFLD. Hepatic CD36 expression is significantly elevated in animal models and patients with NAFLD and is regarded as positively correlated with liver fat content and insulin resistance (6Miquilena-Colina M.E. Lima-Cabello E. Sanchez-Campos S. Garcia-Mediavilla M.V. Fernandez-Bermejo M. Lozano-Rodriguez T. Vargas-Castrillon J. Buque X. Ochoa B. Aspichueta P. et al.Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C.Gut. 2011; 60: 1394-1402Crossref PubMed Scopus (286) Google Scholar). Accumulating evidence indicates that CD36 is not only a fatty acid transporter but also an essential regulator of intracellular fatty acid homeostasis. Recent studies have found that CD36 is involved in fatty acid oxidation by the activation of adenosine monophosphate-activated protein kinase (AMPK) (7Samovski D. Sun J. Pietka T. Gross R.W. Eckel R.H. Su X. Stahl P.D. Abumrad N.A. Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation.Diabetes. 2015; 64: 353-359Crossref PubMed Scopus (126) Google Scholar), suggesting that it modulates fatty acid storage or usage. It has also been reported to function as a pattern recognition receptor that conducts intracellular signals and activates inflammatory pathways such as Toll-like receptor, NF-κB, and c-Jun N-terminal kinase signals to control the chronic metabolic inflammatory response (8Silverstein R.L. Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.Sci. 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This is an pathway of lipid metabolism the pathway of autophagy, degrading lipid and by The free fatty acids by lipophagy from the of of liver lipophagy aggravates hepatic lipid and an increased of NAFLD (14Singh R. Kaushik S. Wang Y. Xiang Y. Novak Komatsu M. K. A.M. lipid 2009; PubMed Scopus Google Scholar). CD36 has been to significantly to the macrophage autophagy L. N. M. L. C. The human a autophagy in that modulates inflammatory 2015; 11: PubMed Scopus Google Scholar), the relationship between CD36 and is The potential role of CD36 in lipophagy has been in NAFLD. a as an and metabolic in metabolic The AMPK pathway cell autophagy and Cell Biol. 2011; PubMed Scopus Google Scholar). The activation of AMPK through phosphorylation of its the by liver kinase or by protein kinase kinase A. K. D. T. M. D. is the kinase in the protein kinase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. K. R. M. M. D. protein kinase of protein kinase in 2: Full Text Full Text PDF PubMed Scopus Google Scholar). In to the role of AMPK as a regulator of evidence has AMPK in the regulation of and pathways such as lipid metabolism, and protein B. B. from to Google Scholar, A. an pathway with and Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In the autophagy AMPK autophagy kinase and to the which is for its function in autophagy The AMPK pathway cell autophagy and Cell Biol. 2011; PubMed Scopus Google Scholar, Zhang M. et phosphorylation of is for of to in 2017; PubMed Scopus Google Scholar, J. M. B. AMPK and autophagy through phosphorylation of Cell Biol. 2011; PubMed Scopus Google Scholar, J. C. W. Liu R. Zhong regulation of by AMPK in and 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). AMPK activates autophagy by the of the of the activation of by and disrupts the between and AMPK J. M. B. AMPK and autophagy through phosphorylation of Cell Biol. 2011; PubMed Scopus Google Scholar). the role of CD36 in fatty acid oxidation to be to CD36 AMPK N.A. CD36 in the and PubMed Scopus Google Scholar). CD36 was to be for the protein a of the CD36 kinase the AMPK kinase and CD36 expression maintains AMPK by to and its from to CD36 activates AMPK its to from the as CD36 is from found that CD36 to the membrane of hepatocytes was associated with AMPK and by hepatic fatty acid which may also from the increased phosphorylation L. Zhang C. Luo X. Wang P. Zhou W. Zhong S. Xie Y. Jiang Y. Yang P. Tang R. CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis.J. Hepatol. 2018; 69: 705-717Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). These studies to the that CD36 may be associated with autophagy through the AMPK In this study, we to the of CD36 in and its in and in that the CD36 has a negative role in the regulation of lipophagy through an This suggests that of the autophagy deficiency by ameliorating CD36 expression in hepatocytes may be a strategy for the treatment of NAFLD. acid was in with a of and and autophagy by autophagosome and which was in with a of and a was in with a of was in and was in and was from and Huh7 in with in a with HepG2 and Huh7 cell with the and CD36, cell also to the lipid and autophagic in cells treatment with for mice on a by Febbraio or mice a or high-fat for In the of CD36 expression in the mice with or CD36 in the and on the for mice in a and on a with free to and mice with free to of treatment to the of the and of to the of for the and of of CD36 in HepG2 cells was by a in for to be with and combined with The was for HepG2 cells in and that the of cells to to Cell with the and Huh7 cells by a to the and liver tissue with protein on an or and a membrane or with for and with and was by in with the and signals an on to cells in for in and in for and in serum for with with and for with and treated with for This was by with lipid cells with a lipid a for a HepG2 or Huh7 cells treated with or and for the of to the the cells or treated with was by of the autophagosome formation with In to autophagic HepG2 cells with or in a the the cells with protein The of the is on the different of and The signal be the the the signal not significantly in In and are as while are as of and in cells that autophagic is while autophagic is only are increased of or and are decreased in cells T. F. Y. Sun T. D. J. Y. Sun D. N. Y. H. J. W. promotes to by 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, C. Zhong W. Zhou J. F. Z. Y. Y. Deng X. B. J. autophagic by an reveals that impairs autophagic in 2012; PubMed Scopus Google Scholar). HepG2 cells in with the for and the was with the with a tissue was in and on a the of autophagy, autophagic as cytoplasmic and cytoplasmic was on a The Cell and from cells of or HepG2 cells on a the of fat treatment on with and the of the with the The was in the and and A and was by the from the in the the cells and protein content was for The was with a to the to cells on cells in for in and in for and by with with and for with a and cells with a was to the was to to the was for are in The of was for in expression was for in liver was in a cell and are expressed as The between was in of significance are in the mice the for to the NAFLD and and steatosis in the livers of mice the with the and free fatty acid contents significantly in the livers of mice the with the CD36 expression and the status of autophagy in we to CD36 and in mice with liver steatosis and and found that the expression of CD36 was increased and was significantly reduced in the mice with liver we an in the protein of of the of autophagy, which was as a of autophagic These that may be a negative between the expression of CD36 and autophagy in we HepG2 and Huh7 cells with to down CD36 expression and an in protein and a in the treatment also an in protein and a in the CD36 expression in the HepG2 cells treatment Meanwhile, we CD36 cell in HepG2 and Huh7 that CD36 in cells with treatment reduced expression and increased autophagy we the in was in HepG2 and Huh7 cells with treatment the in by be due to the induced formation or the decreased of we treated and HepG2 and Huh7 cells with the in the of increased and decreased of in CD36 knockdown and we a in and decreased cells with cells These that an in autophagosome formation in CD36 knockdown autophagic flux. this we and HepG2 cells with that and in and only in and treated with for an in the of and in HepG2 cells with control suggesting an in autophagosome formation the that autophagosome induction was due to increased formation decreased in the CD36 knockdown the relationship between CD36 and autophagy in we CD36, and protein in the livers of CD36 knockout mice and In the and we a in expression and a in in the livers of mice with mice This that the deficiency of CD36 autophagy. CD36 expression with in by a in in autophagic to and in the and and in the livers of mice with in the livers of mice with we found that lipid droplets. we that lipophagy in CD36 knockdown in HepG2 cells a in autophagy coupled with a in lipid droplets. the of intracellular lipid content may be due to decreased fatty acid increased of fatty acid is also for lipid accumulation. Lipophagy engulfing lipid droplets has been to reduced lipid content and increased In this we an in and in HepG2 cells for but a in HepG2 cells treated with we the and found that CD36 knockdown in HepG2 cells also increased and with control HepG2 cells with and the of autophagy the These that CD36 knockdown increased lipophagy and β-oxidation, to lipid and the of autophagy decreased lipophagy and β-oxidation, lipid accumulation. the of lipophagy on lipid we the intracellular in HepG2 cells of the The that CD36 knockdown decreased and the of autophagy in HepG2 cells increased content the protein of a for fatty acid was increased in CD36 mice the and or CD36 knockdown increased protein expression The of was increased in the livers of mice the with mice These that the of CD36 increased fatty acid signaling pathways known to autophagy. of AMPK in the livers of mice the was that of mice the The livers of the a in the phosphorylation of suggesting that the knockout of CD36 the AMPK pathway the AMPK pathway, we and AMPK protein in HepG2 and control with the control was a of in HepG2 cells in the of or in the of confirming that the AMPK pathway was in The kinase is of the that AMPK by the in found that CD36 knockdown cells a protein which was with AMPK The autophagy and AMPK was inhibited by the AMPK in HepG2 cells the of treatment which was by a of lipid AMPK promotes autophagy by or the of However, we found that HepG2 cells in and with cells In addition, the protein and of the not increased in HepG2 and the phosphorylation of was increased in HepG2 but the protein was not increased the of that and induced in HepG2 and Huh7 cells The from liver tissue also this the protein expression and phosphorylation of and in HepG2 and Huh7 CD36 knockdown in HepG2 cells significantly increased expression and phosphorylation and the of AMPK with the expression and phosphorylation of Meanwhile, knockdown of CD36 in Huh7 cells induced expression and phosphorylation suggesting that CD36 knockdown induced autophagy through the we also an induced CD36 suggesting that an induction in may also to the increased autophagy is the of NAFLD. CD36 is an membrane glycoprotein fatty acid uptake (4Hoosdally S.J. Andress E.J. Wooding C. Martin C.A. Linton K.J. The human scavenger receptor CD36: glycosylation status and its role in trafficking and function.J. Biol. Chem. 2009; 284: 16277-16288Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, L. K. P. A. J. A. K. S. H. et to insulin and liver fat in J. PubMed Scopus Google Scholar). In to the function of fatty acid translocase, CD36 an role in signal as a regulator of the inflammatory response and fatty acid β-oxidation, which contributes to the maintenance of fatty acid (7Samovski D. Sun J. Pietka T. Gross R.W. Eckel R.H. Su X. Stahl P.D. Abumrad N.A. Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation.Diabetes. 2015; 64: 353-359Crossref PubMed Scopus (126) Google Scholar). autophagy in the liver has been with of lipid (14Singh R. Kaushik S. Wang Y. Xiang Y. Novak Komatsu M. K. A.M. lipid 2009; PubMed Scopus Google Scholar). In fatty a of can autophagy, such as insulin resistance, and free fatty acids Y. S. H. A. E. T. A. K. K. S. of autophagic function and expression in the liver from patients with non-alcoholic fatty liver Res. PubMed Scopus Google Scholar, H. M. of autophagy PubMed Scopus Google Scholar, L. P. S. hepatic autophagy in promotes and insulin 2010; 11: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the relationship between CD36 and liver autophagy is is the to that CD36 autophagy in livers and is as a engulfing and autophagy hepatic metabolic pathways T. Komatsu M. in the in and Hepatol. 2017; PubMed Scopus Google Scholar). Lipophagy is a of autophagy that of a lipid and it with a (14Singh R. Kaushik S. Wang Y. Xiang Y. Novak Komatsu M. K. A.M. lipid 2009; PubMed Scopus Google Scholar). Lipophagy promotes which is by to and function as a NAFLD. of autophagy and liver steatosis H. M. of autophagy PubMed Scopus Google Scholar, Zhang H. M. X. X. 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R. as a regulator of autophagy by of 2012; PubMed Scopus Google Scholar). reported that induced in and autophagy through AMPK activation and to the and of the M. B. Wang et steatohepatitis protein activation of autophagy and 2017; PubMed Scopus Google Scholar). In this study, was induced CD36 However, the of was not the induced is involved in the increased autophagy and about the pathways of in or in autophagy that CD36 an role in fatty acid β-oxidation, which as a to fatty acid evidence for a by which the of CD36 lipid by of fatty acids. CD36 is a fatty acid translocase, which facilitates the uptake of The cell uptake of and fatty acids also autophagy M. S.A. F. J.M. V. A. R. M. V. et fatty acids J. 2015; PubMed Scopus Google Scholar). cells to fatty acids induced the autophagy pathway, and the fatty acid autophagic that of the we that the uptake of fatty acids in cells and mice also be involved in autophagy. have also to autophagy CD36 expression in hepatocytes treatment and in mice the and with treatment and in mice the was to the of CD36 on in cell and models of NAFLD. that lipophagy in the CD36 knockdown cells with treatment and in the livers of mice the The of lipid uptake on autophagy in cells and mice In we have that knockdown of CD36 in hepatocytes autophagy due to the increased autophagosome formation in autophagic while CD36 autophagy. Lipophagy is increased through an pathway in CD36 knockdown which contributes to the increased and steatosis In to the fatty acid uptake function of CD36, CD36 is a negative regulator of autophagy, and the reduced autophagy is a for lipid in hepatocytes and livers of These findings suggest that attenuating CD36 which enhances the of fatty acids by the induction of lipophagy in to the of fatty acid be a potential therapeutic strategy for fatty liver as as metabolic Febbraio for the with adenosine monophosphate-activated protein kinase cluster of differentiation 36 high-fat long-chain fatty acid liver kinase protein of nonalcoholic fatty liver disease acid CD36 autophagy kinase
Li et al. (Mon,) studied this question.