Methionine and S-adenosylmethionine levels are critical regulators of PP2A activity modulating lipophagy during steatosis

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• 作者：Imanol Zubiete-Franco¹ ; ^&dagger ; ; Juan Luis Garcí ; a-Rodrí ; guez¹ ; ^&dagger ; ; Maite Martí ; nez-Uñ ; a² ; Nuria Martí ; nez-Lopez¹ ; Ashwin Woodhoo¹ ; ⁴ ; Virginia Gutié ; rrez-De Juan¹ ; Naiara Beraza¹ ; ⁴ ; Sergio Lage-Medina³ ; Fernando Andrade³ ; Marta Llarena Fernandez³ ; Luis Aldá ; miz-Echevarrí ; a³ ; David Ferná ; ndez-Ramos¹ ; Juan Manuel Falcon-Perez¹ ; ⁴ ; Fernando Lopitz-Otsoa¹ ; Pablo Fernandez-Tussy¹ ; Lucí ; a Barbier-Torres¹ ; Zigmund Luka⁶ ; Conrad Wagner⁶ ; Carmelo Garcí ; a-Monzó ; n⁵ ; Shelly C. Lu⁷ ; ⁸ ; Patricia Aspichueta² ; José ; Marí ; a Mato¹ ; Marí ; a Luz Martí ; nez-Chantar¹ ; ⁹ ; ^{mlmartinez@cicbiogune.es" class="auth_mail" title="E-mail the corresponding author} ; Marta Varela-Rey¹ ; ^{mvarela.ciberehd@cicbiogune.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GNMT ; glycine N-methyltransferase ; SAMe ; S-adenosylmethionine ; MTOR ; the mammalian target of rapamycin ; PP2A ; protein phosphatase 2A ; LD ; lipid droplets ; MAT ; methionine adenosyltransferase ; SAH ; S-adenosylhomocysteine ; DG ; diglyceride ; TG ; triglycerides ; PEMT ; phosphatidylethanolamine N-methyltransferase ; AHCY ; S-adenosylhomocysteine hydrolase ; NAFLD ; non-alcoholic fatty liver disease ; Deaza ; deazaadenosine ; LC3 ; microtubule-associated light chain 3 ; AST ; aspartate transaminase ; ALT ; alanine tr
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：409-418
• 全文大小：2214 K

文摘

Glycine N-methyltransferase (GNMT) expression is decreased in some patients with severe non-alcoholic fatty liver disease. Gnmt deficiency in mice (Gnmt-KO) results in abnormally elevated serum levels of methionine and its metabolite S-adenosylmethionine (SAMe), and this leads to rapid liver steatosis development. Autophagy plays a critical role in lipid catabolism (lipophagy), and defects in autophagy have been related to liver steatosis development. Since methionine and its metabolite SAMe are well known inactivators of autophagy, we aimed to examine whether high levels of both metabolites could block autophagy-mediated lipid catabolism.

Methods

We examined methionine levels in a cohort of 358 serum samples from steatotic patients. We used hepatocytes cultured with methionine and SAMe, and hepatocytes and livers from Gnmt-KO mice.

Results

We detected a significant increase in serum methionine levels in steatotic patients. We observed that autophagy and lipophagy were impaired in hepatocytes cultured with high methionine and SAMe, and that Gnmt-KO livers were characterized by an impairment in autophagy functionality, likely caused by defects at the lysosomal level. Elevated levels of methionine and SAMe activated PP2A by methylation, while blocking PP2A activity restored autophagy flux in Gnmt-KO hepatocytes, and in hepatocytes treated with SAMe and methionine. Finally, normalization of methionine and SAMe levels in Gnmt-KO mice using a methionine deficient diet normalized the methylation capacity, PP2A methylation, autophagy, and ameliorated liver steatosis.

Conclusions

These data suggest that elevated levels of methionine and SAMe can inhibit autophagic catabolism of lipids contributing to liver steatosis.