Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Lundsgaard, Anne‐Marie; Fritzen, Andreas M.; Nicolaisen, T; Carl, Christian S.; Sjøberg, Kim A.; Raun, Steffen H.; Klein, Anders Bue; Sanchez-Quant, Eva; Langer, Jörg; Ørskov, Cathrine; Clemmensen, Christoffer; Tschöp, Matthias H.; Richter, Erik A.; Kiens, Bente; Kleinert, Maximilian

doi:10.1194/jlr.ra119000177

Cited by 24 publications

(19 citation statements)

References 46 publications

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“…Flux through these metabolic pathways is influenced by different factors, such that, at different physiologic conditions, glucose and FA are used in different proportions and neither are over-accumulated. The dysregulation of the Randle cycle may contribute to the dysregulation of mitochondria and induce cytotoxic effects [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity

Cristo¹,

Calarco²,

Digilio³

et al. 2020

IJMS

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A mismatch between β-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.

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Section: Discussionmentioning

confidence: 99%

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity

Cristo¹,

Calarco²,

Digilio³

et al. 2020

IJMS

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show abstract

“…Etomoxir leads to elevated food intake and reduces liver energy status by reducing adenosine triphosphate/adenosine diphosphate (ATP/ADP) levels in rats [ 59 ]. Furthermore, in mice that were fed a short-term high fat (45%) diet, etomoxir stimulated glucose oxidation, peripheral glucose disposal, and led to elevated circulating fatty acids and circulating triglycerides (TGs) within 5 h of treatment and after several days hepatic steatosis was induced [ 60 ]. Another study that used etomoxir showed that inhibition of CPT I activity by 50% specifically in the liver led to an enlarged liver in a murine model [ 61 ].…”

Section: Fatty Liver Disease and The Role Of L-carnitinementioning

confidence: 99%

The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD)

et al. 2020

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L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.

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“…13 Sustained hyperglycemia without intervention increases risks of macro-and microvascular complications, which may ultimately lead to chronic morbidity or death. 13,14 GLP-1 RAs are commonly indicated for patients who have had sustained hyperglycemia despite treatment with other antihyperglycemic medications, especially for patients who are overweight or obese and have a previous history of cardiovascular disease or with multiple risk factors for cardiovascular disease. 15 GLP-1 RAs exercise 2 major functions that contribute to their antihyperglycemic effects.…”

Section: Mechanism Of Action Of Glp-1mentioning

confidence: 99%

Oral GLP1 Analog: Where Does the Tide Go?

Gardner

Hamdy

2020

Clin Med Insights Endocrinol Diabetes

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T2D is a potentially preventable disease that has been ranked the seventh leading cause of mortality in the United States. There is strong evidence demonstrating that preventing type 2 diabetes is, in many cases, attainable through lifestyle intervention. Unfortunately, prediabetes is mostly overlooked and awareness with diabetes prevention tools is lacking among primary care physicians. Nationally, efforts were not successful in reversing this epidemic even with an array of diabetes medications. Among the most effective medications for T2D are glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have been shown to reduce both A1C and body weight. Dulaglutide, liraglutide and injectable semaglutide also reduced cardiovascular events and cardiovascular mortality in patients with established cardiovascular disease or multiple cardiovascular risk factors. In this review, we will examine the first FDA approved oral GLP-1 RA; semaglutide. Moreover, this review will discuss the potential impact oral semaglutide may have on glycemic control, weight loss and cardiovascular comorbidities. It also examines the factors that may impact patient compliance, including cost, side effects and clinical issues. Finally, it deliberates the optimism surrounding the development of oral semaglutide in the treatment of diabetes as well as related conditions, such as obesity and non-alcoholic fatty liver disease (NAFLD).

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Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

Cited by 24 publications

References 46 publications

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure-Based Virtual Screening to In Vivo Biological Activity

The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD)

Oral GLP1 Analog: Where Does the Tide Go?

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