The possibility that AMPK might be activated in infected cells was examined by immunoblot analysis (Fig

The possibility that AMPK might be activated in infected cells was examined by immunoblot analysis (Fig. in these cells. The combination of attenuated lipid synthesis and enhanced -oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first evidence for enhanced -oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study SB-277011 highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis. and (5,C9) and has been assigned to almost all HCV proteins (core, E1, E2, NS3/4A, NS4B, and NS5A) (5), with core being the most potent inducer (10, 11). Several mechanisms have been identified by which HCV infection can lead to the induction of ROS/RNS, including mitochondrial alterations (12,C16); redistribution of calcium between the ER, cytoplasm, and mitochondria (17,C23); increased expression of NADPH oxidases (24, 25); enhanced expression of CYP2E1 (26,C29); as well as ER stress and the unfolded protein response (10, 18, 22, 30, 31). Oxidative stress also impacts the HCV life cycle at the level of replication and translation and can SB-277011 lead to viral genome heterogeneity, possibly facilitating viral escape from immune detection (32,C36). A better understanding of the cellular events that accompany oxidative/nitrosative stress is likely to contribute to our understanding of the pathogenesis of HCV, as well as provide insight into the HCV life cycle. Oxidative/nitrosative stress has recently emerged as a key activator of the AMP-activated protein kinase (AMPK) signaling system in several cell types, including hepatocytes (37). AMPK is a ubiquitously expressed heterotrimeric serine/threonine kinase complex, consisting of a catalytic -subunit and two regulatory – and -subunits. Once activated, AMPK serves as a metabolic master switch, promoting cellular adaptation and survival in response to environmental or nutritional stressors (38). Full activation of AMPK requires specific phosphorylation (Thr-172) within the activation loop of the catalytic domain of the -subunit by upstream kinases (39). Regardless of the stimulus, activated AMPK turns on ATP-producing processes, such as Rabbit polyclonal to ADNP2 fatty acid oxidation, and turns off ATP-consuming processes, such as lipogenesis (DNL) (40). Thus, the conservation of ATP is the net effect of AMPK activation. Disturbances in lipid metabolism have long been associated with chronic HCV infection (41,C47), and the discovery of a specific HCV strain based on genotype 2 (JFH-1; Japanese fulminant hepatitis-1) that efficiently infects and replicates in cultured Huh7.5/7.5.1 hepatoma cells (48,C51) has provided considerable insight regarding the intimate link between host cell lipids and HCV infection, at virtually each stage of the HCV replication cycle (45). Providing there are sufficient levels of viral replication, an HCV-induced cytopathic effect is readily observed with this system and is characterized by massive cell death due to apoptosis, which strongly correlates with cell cycle arrest and the induction of numerous genes involved in anti-oxidative stress response (7, 9, 52,C54). Rapidly proliferating cells require a constant supply of lipids for membrane biogenesis and protein modifications (55), and HCV replication is expected to increase this demand further (45). However, the demand for lipid synthesis is expected to be SB-277011 lower in growth-arrested cells (55), albeit with predictable consequences to.

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