Roles and Regulation of Ketogenesis in Cultured Astroglia and Neurons Under Hypoxia and Hypoglycemia

Abstract

Exogenous ketone bodies (KBs), acetoacetate (AA), and β-hydroxybutyrate (BHB) act as alternative energy substrates in neural cells under starvation. The present study examined the endogenous ketogenic capacity of astroglia under hypoxia with/without glucose and the possible roles of KBs in neuronal energy metabolism. Cultured neurons and astroglia were prepared from Sprague-Dawley rats. Palmitic acid (PAL) and l-carnitine (LC) were added to the assay medium. The 4- to 24-hr production of AA and BHB was measured using the cyclic thio-NADH method. 14C-labeled acid-soluble products (KBs) and 14CO2 produced from [1-14C]PAL were also measured. l-[U-14C]lactic acid ([14C]LAC), [1-14C]pyruvic acid ([14C]PYR), or β-[1-14C]hydroxybutyric acid ([14C]BHB) was used to compare the oxidative metabolism of the glycolysis end products with that of the KBs. Some cells were placed in a hypoxic chamber (1% O2). PAL and LC induced a higher production of KBs in astroglia than in neurons, while the CO2 production from PAL was less than 5% of the KB production in both astroglia and neurons. KB production in astroglia was augmented by the AMP-activated protein kinase activators, AICAR and metformin, as well as hypoxia with/without glucose. Neuronal KB production increased under hypoxia in the absence of PAL and LC. In neurons, [14C]LAC and [14C]PYR oxidation decreased after 24 hr of hypoxia, while [14C]BHB oxidation was preserved. Astroglia responds to ischemia in vitro by enhancing KB production, and astroglia-produced KBs derived from fatty acid might serve as a neuronal energy substrate for the tricarboxylic acid cycle instead of lactate, as pyruvate dehydrogenase is susceptible to ischemia.

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

“…Ketone bodies are highly efficient fuels that require less O 2 (Veech, 2004). They serve as a preferred energy source for cells of the nervous system subjected to hypoxia and hypoglycemia (Takahashi et al, 2014). Ketone bodies could be synthesized and secreted by other cells (Martinez-Outschoorn et al, 2012), or they could be produced by TILs directly as suggested by increased transcript levels of Bdh1, a key enzyme in ketone body metabolism, and enhanced intensities of ketone bodies in CD8 + TILs from late-stage tumors.…”

Lauric Acid Stimulates Ketone Body Production in the KT-5 Astrocyte Cell Line

“…shown that primary astrocytes can also oxidize fatty acids and generate KBs, suggesting that such central production of KBs in astrocytes may compensate for a diminished energy supply from glucose in nearby neurons 13,17 .…”

“…As they are located around intraparenchymal blood capillaries, astrocytes are the first cellular barrier on the route to brain tissue encountered by nutrients and other substances. Accumulating evidence suggests that fatty acids can cross the blood-brain barrier and that astrocytes have a greater preference for fatty acids as their primary energy fuel and produce larger amounts of KBs, which are taken up by neighboring neurons and serve as oxidative fuels during hypoxia and hypoglycemia 12,13 . Furthermore, the major regulatory and rate-limiting step of ketogenesis in astrocytes is carnitine palmitoyltransferase I CPT-I 14 , which can be bypassed by MCFAs 8,9 .…”

Mechanisms of cell–cell interaction in oligodendrogenesis and remyelination after stroke

“…When persistent mild hyperketonemia is observed in neonatal rats and human newborns, ketone bodies serve as an indispensable source of energy and cholesterol synthesis for extrahepatic tissues and especially for the developing brain (Koper et al, 1981). Even in the adult brain, ketogenesis may occur when glucose availability is limited, such as during starvation, prolonged hypoglycemia, or ischemia (Takahashi et al, 2014). In addition to oligodendrocyte lineage cells, other cells such as astrocytes and neurons can be a source of cholesterol (Guzman and Blazquez, 2001).…”