bims-glecem 2023-09-24 papers

Issue of 2023–09–24
three papers selected by
Dipsikha Biswas, Københavns Universitet

Genes Nutr. 2023 Sep 18. 18(1): 15

From common to rare: repurposing of bempedoic acid for the treatment of glycogen storage disease type 1.

Hypoketotic hypoglycaemia is a biochemical hallmark of glycogen storage disease type 1 (GSD1). This is due to inhibition of carnitine-palmitoyl transferase 1 by malonyl-CoA. This inhibits the influx of long-chain fatty acids into the mitochondrial matrix for fatty acid oxidation. This leads to reduced hepatic ketogenesis and impaired energy production in the liver and kidney. Hypoketotic hypoglycaemia may result in CNS symptoms due to energy depletion.Recently, it was reported that enzymes involved in mitochondrial long-chain fatty acid oxidation are upregulated in PBMC from patients suffering from GSD1.I suggest that administration of the prodrug bempedoic acid results in reduced production of malonyl-CoA by inhibiting the ATP-citrate lyase, thus releasing the block of mitochondrial long-chain fatty acid influx. These fatty acids could make use of the increased capacity of fatty acid oxidation as observed in PBMC recently. In the liver, ketogenesis is activated, and energy production is increased in both the liver and kidney. This could result in improved metabolic control and avoidance of cerebral energy depletion.Bempedoic acid is approved as medication in adult patients with hypercholesterolaemia and mixed dyslipidaemia. Repurposing bempedoic acid for the use in GSD1 may improve metabolic control in GSD1.

Keywords: Bempedoic acid; Glycogen storage diseases type 1; Ketone bodies; Malonyl-CoA

DOI: https://doi.org/10.1186/s12263-023-00733-2

Curr Med Sci. 2023 Sep 18.

Glycogen Synthase Kinase-3β, NLRP3 Inflammasome, and Alzheimer's Disease.

Yue-Ran Jia, Zi-Qing Guo, Qian Guo, Xiao-Chuan Wang.

Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide. Because of the progressive neurodegeneration, individual cognitive and behavioral functions are impaired, affecting the quality of life of millions of people. Although the exact pathogenesis of AD has not been fully elucidated, amyloid plaques, neurofibrillary tangles (NFTs), and sustaining neuroinflammation dominate its characteristics. As one of the major tau kinases leading to hyperphosphorylation and aggregation of tau, glycogen synthase kinase-3β (GSK-3β) has been drawing great attention in various AD studies. Another research focus of AD in recent years is the inflammasome, a multiprotein complex acting as a regulator in immunological reactions to exogenous and endogenous danger signals, of which the Nod-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome has been studied mostly in AD and proven to play a significant role in AD development by its activation and downstream effects such as caspase-1 maturation and interleukin (IL)-1β release. Studies have shown that the NLRP3 inflammasome is activated in a GSK-3β-dependent way and that inhibition of the NLRP3 inflammasome downregulates GSK-3β, suggesting that these two important proteins are closely related. This article reviews the respective roles of GSK-3β and the NLRP3 inflammasome in AD as well as their relationship and interaction.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; glycogen synthase kinase-3β

DOI: https://doi.org/10.1007/s11596-023-2788-4

Am J Physiol Cell Physiol. 2023 Sep 18.

High-Fat Ketogenic Diets and Ketone Monoester Supplements Differentially Affect Substrate Metabolism during Aerobic Exercise.

Lee M Margolis, Stefan M Pasiakos, Emily E Howard.

Chronically adhering to high-fat ketogenic diets or consuming ketone monoester supplements elicits ketosis. Resulting changes in substrate metabolism appear to be drastically different between ketogenic diets and ketone supplements. Consuming a ketogenic diet increases fatty acid oxidation with concomitant decreases in endogenous carbohydrate oxidation. Increased fat oxidation eventually results in an accumulation of circulating ketone bodies, which are metabolites of fatty acids that serve as an alternative source of fuel. Conversely, consuming ketone monoester supplements rapidly increases circulating ketone body concentrations that typically exceed those achieved by adhering to ketogenic diets. Rapid increases in ketone body concentrations with ketone monoester supplementation elicits a negative feedback inhibition that reduces fatty acid mobilization during aerobic exercise. Supplement-derived ketosis appears to have minimal impact on sparing of muscle glycogen or minimizing of carbohydrate oxidation during aerobic exercise. This review will discuss the substrate metabolic and associated aerobic performance responses to ketogenic diets and ketone supplements.

Keywords: Aerobic performance; endurance exercise; glycogen; high-fat, low-carbohydrate diet; β-hydroxybutyrate

DOI: https://doi.org/10.1152/ajpcell.00359.2023