Autophagy regulates sphingolipid levels in the liver

Abstract

Journal of Lipid Research Volume 55, 20142521 the metabolic pathway ( 3 ). Ceramide undergoes anabolic reactions to generate sphingomyelin and various glycosphingolipids, or catabolic reactions, which lead to the generation of sphingosine and sphingosine-1-phosphate (S1P). Alterations in ceramide metabolism have been implicated in many pathophysiologies, including aging ( 4-6 ), neurodegeneration ( 7,8 ), metabolic diseases ( 9-15 ), cancer (16)(17)(18)(19)(20), and stress responses ( 5 ). However, the mechanisms that regulate cellular ceramide levels under physiologic and pathophysiologic conditions are still not well-understood.Changes in the levels of ceramide and other sphingolipid metabolites have been shown to affect macroautophagy (referred to hereafter as autophagy) in a variety of cell types ( 21-27 ). Autophagy is a catabolic process that starts with the generation of a double-membrane cup-like phagophore from the ER or other sources ( 28, 29 ); the phagophore then captures cellular material and matures into an autophagosome that will subsequently fuse with a lysosome to form an autolysosome, enabling degradation of the engulfed material. This process is crucial for removal of pathogens and damaged proteins and organelles, as well as for the reutilization of nutrients to generate energy and maintain homeostasis. Clearance of toxic or defective cellular components protects from degenerative, metabolic, and infl ammatory diseases ( 30 ). Some forms of autophagy are specifi c, uniquely targeting mitochondria (mitophagy) ( 31 ), segments of the ER (ER-phagy or reticulophagy) ( 32 ), or triglyceride stores (lipophagy) ( 33 ) for degradation. Impaired autophagy is encountered, along with increased ceramide levels, in a number of pathophysiologic conditions, including aging ( 34, 35 ), neurodegeneration ( 36, 37 ), obesity ( 10 ), and type 2 diabetes ( 9 ).Abstract Sphingolipid levels are tightly regulated to maintain cellular homeostasis. During pathologic conditions such as in aging, infl ammation, and metabolic and neurodegenerative diseases, levels of some sphingolipids, including the bioactive metabolite ceramide, are elevated. Sphingolipid metabolism has been linked to autophagy, a critical catabolic process in both normal cell function and disease; however, the in vivo relevance of the interaction is not wellunderstood. Here, we show that blocking autophagy in the liver by deletion of the Atg7 gene, which is essential for autophagosome formation, causes an increase in sphingolipid metabolites including ceramide. We also show that overexpression of serine palmitoyltransferase to elevate de novo sphingolipid biosynthesis induces autophagy in the liver. The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in the liver. Dysfunctional autophagy may be an underlying mechanism causing elevations in ceramide that may contribute to pathogenesis in diseases. Sphingolipids are a structurally and functionally di...

Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner

“…It was previously observed that an increase in acid ceramidase, which is a lysosomal enzyme, resulted in elevated lysosomal density and increased levels of autophagy (40). Autophagy has been demonstrated to serve as a cellular mechanism to limit ceramide levels in the liver (41) and also occurs as a consequence of increased sphingolipid synthesis in RAW264.7 cells following TLR4 stimulation (42). In contrast to these studies, we did not detect an increase in overall ceramide synthesis but rather a shift in composition (Fig.…”

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

“…[38][39][40] Moreover, correlations of NASH-associated CpG sites with mRNA expression of CEACAM1, SH3BP4 (encoding transferrin receptor-trafficking protein), and NAT2 also support a role for our findings relating differential DNA methylation in NASH with impaired insulin signaling/action. [41][42][43][44][45][46][47] The mechanisms that could alter DNA methylation in the insulin-resistant liver remain to be elucidated. However, these differences in methylation may be due to altered levels of enzymes responsible for adding or removing methyl groups to the genome, such as DNMTs.…”

Regulation and Functions of Autophagic Lipolysis

“…The bioactive sphingolipid ceramide is increased in Atg7 knockout mouse liver [43]. Autophagy increased when sphingolipid de novo synthesis was upregulated, indicating that lipid degradation was activated to prevent excessive sphingolipid accumulation.…”