Carta Acesso aberto Revisado por pares

Regulation of lipophagy in NAFLD by cellular metabolism and CD36

2019; Elsevier BV; Volume: 60; Issue: 4 Linguagem: Inglês

10.1194/jlr.c093674

ISSN

1539-7262

Autores

Dmitri Samovski, Nada A. Abumrad,

Tópico(s)

Endoplasmic Reticulum Stress and Disease

Resumo

Nonalcoholic fatty liver disease (NAFLD) progresses in a subset of patients to nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis, and increased risk of hepatocellular carcinoma (1Hardy T. Oakley F. Anstee Q.M. Day C.P. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum.Annu. Rev. Pathol. 2016; 11: 451-496Crossref PubMed Scopus (343) Google Scholar). A better understanding of the factors involved in the development, progression, or resolution of hepatic steatosis and NAFLD will expand the repertoire of tools available for treatment of NASH and its associated comorbidities. The hallmark of NAFLD is an excessive accumulation of liver triglycerides in the form of intracellular lipid droplets (LDs). Lipid homeostasis is impaired, because lipid uptake or synthesis exceeds lipid oxidation or from impaired lipid secretion via VLDLs. As a result, LD biogenesis surpasses LD catabolism (2Gluchowski N.L. Becuwe M. Walther T.C. Farese Jr., R.V. Lipid droplets and liver disease: from basic biology to clinical implications.Nat. Rev. Gastroenterol. Hepatol. 2017; 14: 343-355Crossref PubMed Scopus (282) Google Scholar). Lipid mobilization from LDs in response to nutritional or hormonal cues occurs through two main pathways; by lipolysis through lipases acting at the LD surface and by a form of autophagy termed lipophagy. Autophagy is the orderly degradation and recycling of cellular components by lysosomes in response to stresses, such as nutrient deprivation or the accumulation of damaged proteins or organelles (3Martinez-Lopez N. Singh R. Autophagy and lipid droplets in the liver.Annu. Rev. Nutr. 2015; 35: 215-237Crossref PubMed Scopus (185) Google Scholar, 4Ohsumi Y. Historical landmarks of autophagy research.Cell Res. 2014; 24: 9-23Crossref PubMed Scopus (648) Google Scholar, 5Levine B. Klionsky D.J. Development by self-digestion: molecular mechanisms and biological functions of autophagy.Dev. Cell. 2004; 6: 463-477Abstract Full Text Full Text PDF PubMed Scopus (3189) Google Scholar). The type of cargo delivered to lysosomes is used to classify autophagy. For example, mitophagy and pexophagy refer to mitochondrial and peroxisomal cargos, respectively, and likewise, lipophagy refers to lipid cargo. Lipophagy involves incorporation of small LDs into autophagosomes for delivery to lysosomes, where triglycerides are degraded by lysosomal acid lipase, releasing FAs for mitochondrial oxidation and ATP generation (2Gluchowski N.L. Becuwe M. Walther T.C. Farese Jr., R.V. Lipid droplets and liver disease: from basic biology to clinical implications.Nat. Rev. Gastroenterol. Hepatol. 2017; 14: 343-355Crossref PubMed Scopus (282) Google Scholar, 3Martinez-Lopez N. Singh R. Autophagy and lipid droplets in the liver.Annu. Rev. Nutr. 2015; 35: 215-237Crossref PubMed Scopus (185) Google Scholar). Autophagy and lipophagy are dynamic processes that are tightly linked to the cellular metabolic state. Nutrient deprivation is a potent inducer of autophagy (6Adachi A. Koizumi M. Ohsumi Y. Autophagy induction under carbon starvation conditions is negatively regulated by carbon catabolite repression.J. Biol. Chem. 2017; 292: 19905-19918Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar), while chronic high fat feeding (7Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2635) Google Scholar) or overnutrition, as in the ob/ob mouse (8Yang L. Li P. Fu S. Calay E.S. Hotamisligil G.S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.Cell Metab. 2010; 11: 467-478Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar), are associated with autophagy suppression. Autophagy plays an important role in hepatocyte LD turnover, as supported by the findings that mice lacking the autophagy gene Atg7 in the liver display increased hepatic triglyceride content and reduced rates of both mitochondrial FA oxidation and VLDL secretion (7Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2635) Google Scholar). In ob/ob mice, overexpression of ATG7 in the liver, by contrast, effectively prevents hepatic steatosis (8Yang L. Li P. Fu S. Calay E.S. Hotamisligil G.S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.Cell Metab. 2010; 11: 467-478Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar). In this issue of the Journal of Lipid Research, Li et al. (9Li Y. Yang P. Zhao L. Chen Y. Zhang X. Zeng S. Wei L. Varghese Z. Moorhead J.F. Chen Y. CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway.J. Lipid Res. 2019; 60: 844-855Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) identify the FA transporter CD36 as a negative regulator of lipophagy in hepatocytes. The authors observe that livers of mice fed a high-fat diet have reduced autophagy and increased CD36 protein. Although these two observations have been previously reported (7Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2635) Google Scholar, 8Yang L. Li P. Fu S. Calay E.S. Hotamisligil G.S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.Cell Metab. 2010; 11: 467-478Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar, 9Li Y. Yang P. Zhao L. Chen Y. Zhang X. Zeng S. Wei L. Varghese Z. Moorhead J.F. Chen Y. CD36 plays a negative role in the regulation of lipophagy in hepatocytes through an AMPK-dependent pathway.J. Lipid Res. 2019; 60: 844-855Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 10Zhao 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), the potential relationship between CD36 and autophagy had not been explored. The authors show that CD36 overexpression in hepatoma-derived cell lines (HepG2 and Huh7) decreases autophagy and increases LD content, while CD36 knockdown has the opposite effect. Cd36 deletion in mice resulted in increased autophagy, which was abolished by CD36 rescue. The mechanism proposed for the negative effect of CD36 on autophagy is its action to suppress adenosine monophosphate-activated protein kinase (AMPK) (11Samovski 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 beta-oxidation.Diabetes. 2015; 64: 353-359Crossref PubMed Scopus (126) Google Scholar), which is a major enhancer of autophagy (12Mihaylova M.M. Shaw R.J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism.Nat. Cell Biol. 2011; 13: 1016-1023Crossref PubMed Scopus (1980) Google Scholar). Li et al. show that CD36 deficiency increases autophagy via activation of AMPK, which enhances activity of uncoordinated 51-like kinase 1 (ULK1) and Beclin1, two key protein complexes important for autophagosome biogenesis. Both ULK1 and Beclin1 are activated through AMPK phosphorylation (13Mercer T.J. Gubas A. Tooze S.A. A molecular perspective of mammalian autophagosome biogenesis.J. Biol. Chem. 2018; 293: 5386-5395Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). CD36 is a membrane receptor that recognizes multiple lipid (FAs, lipoproteins) and nonlipid (thrombospondins, collagen) ligands. CD36 interaction with its ligands triggers intracellular signaling that connects to a range of pathways involving metabolism, immunity, and matrix remodeling (14Pepino M.Y. Kuda O. Samovski D. Abumrad N.A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism.Annu. Rev. Nutr. 2014; 34: 281-303Crossref PubMed Scopus (326) Google Scholar, 15Magdaleno F. Arriazu E. Ruiz de Galarreta M. Chen Y. Ge X. Conde de la Rosa L. Nieto N. Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis.J. Hepatol. 2016; 65: 963-971Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 16Canton J. Neculai D. Grinstein S. Scavenger receptors in homeostasis and immunity.Nat. Rev. Immunol. 2013; 13: 621-634Crossref PubMed Scopus (525) Google Scholar). An established physiological function of CD36 is its facilitation of the cellular uptake of FAs, a process implicated in cellular LD accumulation. Less well appreciated is the regulatory role of CD36 signaling in cellular metabolism. CD36 associates with various metabolic proteins and influences protein associations and signal transduction by controlling localization and activity of a number of partner kinases (14Pepino M.Y. Kuda O. Samovski D. Abumrad N.A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism.Annu. Rev. Nutr. 2014; 34: 281-303Crossref PubMed Scopus (326) Google Scholar). Among the CD36-associated metabolic proteins are AMPK, LKB1, the insulin receptor (IR), PI3, and src kinases, notably Fyn. CD36 expression has been shown to suppress AMPK activation (11Samovski 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 beta-oxidation.Diabetes. 2015; 64: 353-359Crossref PubMed Scopus (126) Google Scholar) while it enhances insulin signaling (17Samovski D. Dhule P. Pietka T. Jacome-Sosa M. Penrose E. Son N.H. Flynn C.R. Shoghi K.I. Hyrc K.L. Goldberg I.J. Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling.Diabetes. 2018; 67: 1272-1284Crossref PubMed Scopus (28) Google Scholar). These effects are mediated by Fyn phosphorylation of LKB1 and IR, resulting in opposite effects on the signaling activity of these proteins. FA addition reverses the effects of CD36 on AMPK and IR, reducing insulin-stimulated glucose metabolism and activating AMPK. Thus, the influence of CD36 on cellular preference between glucose and FAs provides a basis for its relationship to autophagy, which is coupled to the nutritional state of the cell. Previous studies suggest that lipid regulation of autophagy is likely to differ in the healthy, as compared with the fatty, liver. In contrast to chronic lipid exposure, which suppresses autophagy, acute lipid addition activates autophagy, which helps reestablish homeostasis by enhancing lipid consumption (7Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2635) Google Scholar). The enhanced respiratory metabolism correlates positively with the extent of autophagy induction (6Adachi A. Koizumi M. Ohsumi Y. Autophagy induction under carbon starvation conditions is negatively regulated by carbon catabolite repression.J. Biol. Chem. 2017; 292: 19905-19918Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Oleic acid treatment of hepatocytes activates lipophagy (7Singh R. Kaushik S. Wang Y. Xiang Y. Novak I. Komatsu M. Tanaka K. Cuervo A.M. Czaja M.J. Autophagy regulates lipid metabolism.Nature. 2009; 458: 1131-1135Crossref PubMed Scopus (2635) Google Scholar) and both palmitic and oleic acids acutely stimulate autophagy in vitro and in vivo (18Niso-Santano M. Malik S.A. Pietrocola F. Bravo-San Pedro J.M. Marino G. Cianfanelli V. Ben-Younes A. Troncoso R. Markaki M. Sica V. Unsaturated fatty acids induce non-canonical autophagy.EMBO J. 2015; 34: 1025-1041Crossref PubMed Scopus (132) Google Scholar). Interestingly, AMPK depletion only inhibited palmitic acid induction of autophagy, suggesting that distinctive mechanisms mediate effects of saturated versus unsaturated FAs (18Niso-Santano M. Malik S.A. Pietrocola F. Bravo-San Pedro J.M. Marino G. Cianfanelli V. Ben-Younes A. Troncoso R. Markaki M. Sica V. Unsaturated fatty acids induce non-canonical autophagy.EMBO J. 2015; 34: 1025-1041Crossref PubMed Scopus (132) Google Scholar). Li et al. mention that addition of palmitic acid to cells depleted of CD36 did not alter AMPK activation (Fig. 6G). However, this would be expected because palmitate activation of AMPK requires CD36 (11Samovski 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 beta-oxidation.Diabetes. 2015; 64: 353-359Crossref PubMed Scopus (126) Google Scholar). Thus, a limitation of the study is that it only addresses autophagy in mice chronically fed a high-fat diet and does not shed light on autophagy regulation under normal conditions. In summary, the available data suggest that lipids activate autophagy to increase oxidative metabolism, but this adaptive response fails with chronic lipid exposure (Fig. 1). CD36 expression is normally low in hepatocytes, but both expression and membrane localization are increased in NAFLD (10Zhao 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). A recent report showed that this might be caused by augmented CD36 palmitoylation, which impairs the ability of CD36 to enhance FA oxidation, a process important for autophagy induction. The report further showed that inhibition of CD36 palmitoylation prevents development of steatohepatitis (10Zhao 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). CD36 is subject to a number of posttranslational modifications, and it is possible that targeting these modifications could afford a more specific approach for controlling the function and metabolic effects of the protein.

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