Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • br ACL A Metabolic Checkpoint

    2024-06-22


    ACL: A Metabolic Checkpoint for Sensing Excess Nutrients? During normal transitions between fasting and feeding, cells maintain energy homeostasis by integrating energy and nutrient status signals at key metabolic nodes, coordinating multiple processes. For example, the AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that responds to energy deficit by mediating regulatory phosphorylation of numerous substrates including acetyl-CoA carboxylase (ACC) and HMG-CoA reductase 36, 37, 38, 39 (Figure 2). The net result of these phosphorylation events is a switch from energy-consuming processes (e.g., cholesterol, fatty acid, and protein synthesis) to energy-producing processes (e.g., fatty LX-1031 β-oxidation, glucose uptake), and restored energy balance. Under conditions of prolonged energetic stress such as exercise training or caloric restriction [40], this pathway promotes mitochondrial biogenesis, an effect which is potentiated by activating Sirtuin1 (SIRT1)-dependent deacetylation of critical transcription factors and coactivators such as p53 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) 41, 42. As such, AMPK and SIRT1 cooperate to elicit both acute and chronic metabolic adaptations to reverse cellular energy deficits and maintain metabolic flexibility [41]. Despite the importance of activating AMPK–SIRT1 under energetic stress, the ability of this pathway to reprogram cellular metabolism under conditions of nutrient excess appears to be minimal, as evidenced by the relatively benign metabolic phenotype of Ampk and Sirt1 genetic loss-of-function mouse models fed hypercaloric high-fat diets (HFDs) 40, 43. However, recent reports suggest that extramitochondrial acetyl-CoA concentrations might impact protein acetylation and exert influence over metabolism by limiting the supply of substrate for acetyltransferases such as GCN5, independently of the AMPK–SIRT deacetylation axis 20, 44, 45. This is supported by studies showing that the acetylation status of multiple transcription factors, enzymes, and histones is closely linked to extramitochondrial acetyl-CoA concentrations, and that this regulatory mechanism could be critical for maintaining metabolic flexibility during changes in nutritional status (Figure 2) 20, 41, 44, 46. In contrast to mitochondria, the cytosolic acetyl-CoA pool can exchange with the acetyl-CoA nuclear pool via the nuclear pore complex [47] (therefore, often regarded as one nucleocytosolic pool). As mentioned, ACL is the primary enzyme that generates cytosolic acetyl-CoA by catalyzing the cleavage of citrate produced from the mitochondrial metabolism of macronutrients (see Figure I in Box 1). Because cytosolic acetyl-CoA is also the final common substrate supporting the conversion of excess mitochondrial metabolism of nutrients to both cholesterol and fatty acid biosynthesis for storage, ACL potentially provides a logical checkpoint to signal nutrient availability by also promoting metabolic adaptations via substrate-level protein acetylation (Figure 2) [46]. Indeed, this was demonstrated in mammalian cells, where nuclear ACL-derived acetyl-CoA was found to be required for GCN5-dependent histone acetylation in response to both growth factor stimulation and glucose availability [20]. Moreover, in primary adipocytes, this pathway was also required for glucose-induced transcriptional regulation of select genes such as Glut4, important for modulating the increase of glucose uptake [20]. It is noteworthy that GCN5 also directly acetylates and inhibits non-histone proteins such as the transcription factor, PGC-1α 48, 49, which suggests an important link between nucleocytosolic acetyl-CoA levels and mitochondrial biogenesis [41], and potentially ACL. In mice, GCN5-dependent modulation of PGC-1α acetylation and activity has been shown to reciprocally regulate energy expenditure in response to caloric excess or caloric restriction [50]. Because GCN5 is dependent on ACL for acetyl-CoA substrate, ACL activity might also reciprocally control PGC-1α activity by providing acetyl-CoA for its acetylation when energy/substrate levels are high, or by limiting its acetylation when energy/substrate levels are low. When coupled with the AMPK–SIRT1 energy sensing pathway, cells might then integrate changes in ACL activity with cellular energy status to promote appropriate funneling of macronutrients toward energy production (fatty acid β-oxidation) or storage (lipid synthesis), while ensuring sufficient metabolic capacity (e.g., mitochondrial biogenesis) upon changing energy/nutritional status (Figure 2). This raises the intriguing possibility that targeting ACL could potentially offer a point of therapeutic intervention aimed at restoring metabolic homeostasis by short-circuiting chronic signals of caloric/energy excess and enhancing mitochondrial function. However, whether the suppression of ACL results in PGC-1α activation and improved mitochondrial function in the context of metabolic disease has not been studied and warrants investigation.