Fatal Liver Failure in an Adult Patient with Acute Lymphoblastic Leukemia following Treatment with &lt;i&gt;L&lt;/i&gt;-Asparaginase

Bodmer, Michael; Sulz, Michael Christian; Stadlmann, Sylvia; Droll, Armin; Terracciano, Luigi; Krähenbühl, Stephan

doi:10.1159/000095827

Cited by 54 publications

(39 citation statements)

References 51 publications

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“…Microvesicular steatosis has been previously reported under conditions of altered fatty acid metabolism ( 52,53 ). The marked increase in CD36 mRNA in livers of ob/ob compared with WT mice has been described previously ( 10,35 ), a fi nding we confi rmed and extended to protein levels.…”

Section: Discussionmentioning

confidence: 92%

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Nassir

Adewole

Brunt

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org novo FA synthesis or de novo lipogenesis (DNL), decreased FA oxidation, and reduced secretion of VLDLs ( 1, 2 ).CD36 is a class B scavenger receptor that plays an important role in several pathways of FA utilization. The protein is expressed in many cell types, including lingual taste bud cells, enterocytes, adipocytes, myocytes, and immune cells. On taste bud cells, CD36 is important for FA recognition and fat perception ( 3, 4 ). In skeletal muscle, heart, and adipose tissue, CD36 facilitates tissue FA uptake and utilization ( 5, 6 ). In the small intestine, it is important for chylomicron secretion ( 7 ) and for FA-induced release of secretin and cholecystokinin ( 8 ). In the liver, CD36 is expressed on endothelial, parenchymal, and Kupffer cells ( 9 ). Basal expression of liver CD36 is low but increases in experimental models of hepatic steatosis, such as genetic obesity and highfat feeding ( 10, 11 ) or following activation of the prosteatotic transcription factors liver X receptor (LXR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AHR) by xenobiotics, bacteria, or cytokines ( 12 ). Mice fed a highfat diet have increased liver CD36 expression associated with enhanced hepatic FA uptake and TG accumulation, and these are prevented by CD36 deletion ( 11 ). Interestingly, however, the prosteatotic effects of a high-fructose diet, which enhances DNL and TG accumulation in the liver ( 13 ), are exacerbated by CD36 deletion ( 14 ).In humans with nonalcoholic fatty liver disease (NAFLD), hepatic CD36 positively correlates with liver fat content ( 15 ), but its relationship to output of VLDL suggests that its impact on hepatic FA metabolism might not be limited to enhancing FA fl ux and TG accumulation. NAFLD is Abstract Recent findings described the role of CD36-mediated signaling in regulating cellular calcium and the release of various bioactive molecules, including the prostaglandins, neurotransmitters, cholecystokinin, and secretin. Here we document the role of CD36 in the secretion of hepatic VLDL. CD36 deletion resulted in 60% suppression of VLDL output in vivo, and VLDL secretion was reduced in vitro using incubated liver slices. The effect of CD36 deletion was mediated by enhancing formation of hepatic prostaglandins D2, F2, and E2. Treatment of CD36-defi cient slices with inhibitors of cyclooxygenases reversed the reduction in triglyceride secretion. We also examined the effect of CD36 deletion on the obesity-associated spontaneous steatosis of the ob/ob mouse that is driven by enhanced de novo lipogenesis. Homozygous ob/ob mice lacking CD36 ( ob-CD36 ؊ / ؊ ) were generated and studied for hepatic triglyceride accumulation and VLDL secretion. Livers of ob/ob mice were steatotic as expected and had 5-fold more CD36 on Kupffer cells and hepatocytes. CD36 deletion exacerbated the steatosis by impairing hepatic triglyceride and apoB secretion through increasing prostaglandin levels. These fi ndings suggest an unappreciated role of CD36 in reg...

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Section: Discussionmentioning

confidence: 92%

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Nassir

Adewole

Brunt

et al. 2013

Journal of Lipid Research

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“…Asparaginase has a signifi cant adverse eff ect profi le, including risk of thrombosis, bleeding, pancreatic hypersensitivity, and hepatotoxicity. Asparaginase toxicity on the liver can be quite severe and may produce a rapid functional decline and even lead to death (1). Typical therapy for this adverse event is supportive care.…”

mentioning

confidence: 99%

Successful Treatment of Pegaspargase-Induced Acute Hepatotoxicity with Vitamin B Complex and L-Carnitine

Karur

Herrington

et al. 2016

Baylor University Medical Center Proceedings

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“…Hepatic steatosis and dysfunction leading to liver failure and secondarily to coagulopathy and thromboembolism are among the most serious side effects associated with asparaginase treatment (10,23). The data presented in this effort describe how the GCN2-directed AAR controls the ability of the liver to adapt to asparaginase.…”

Section: Discussionmentioning

confidence: 99%

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

Wilson

Lennox

She

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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The antileukemic agent asparaginase triggers the amino acid response (AAR) in the liver by activating the eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2). To explore the mechanism by which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent liver dysfunction during continued asparaginase treatment, wild-type and Gcn2 null mice were injected once daily with asparaginase or phosphate buffered saline for up to 14 days. Asparaginase induced mRNA expression of multiple AAR genes and greatly increased circulating concentrations of the metabolic hormone fibroblast growth factor 21 (FGF21) independent of food intake. Loss of Gcn2 precluded mRNA expression and circulating levels of FGF21 and blocked mRNA expression of multiple genes regulating lipid synthesis and metabolism including Fas, Ppara, Pparg, Acadm, and Scd1 in both liver and white adipose tissue. Furthermore, rates of triglyceride export and protein expression of apolipoproteinB-100 were significantly reduced in the livers of Gcn2 null mice treated with asparaginase, providing a mechanistic basis for the increase in hepatic lipid content. Loss of AAR-regulated antioxidant defenses in Gcn2 null livers was signified by reduced Gpx1 gene expression alongside increased lipid peroxidation. Substantial reductions in antithrombin III hepatic expression and activity in the blood of asparaginase-treated Gcn2 null mice indicated liver dysfunction. These results suggest that the ability of the liver to adapt to prolonged asparaginase treatment is influenced by GCN2-directed regulation of FGF21 and oxidative defenses, which, when lost, corresponds with maladaptive effects on lipid metabolism and hemostasis.

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Fatal Liver Failure in an Adult Patient with Acute Lymphoblastic Leukemia following Treatment with <i>L</i>-Asparaginase

Cited by 54 publications

References 51 publications

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Successful Treatment of Pegaspargase-Induced Acute Hepatotoxicity with Vitamin B Complex and L-Carnitine

GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment

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