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Effects of asparaginases and L-carnitine on Western-diet-induced hepatosteatosis in mice.

ABSTRACT: Background: Asparaginases are common chemotherapeutic agents used for the treatment of acute lymphoblastic leukemia as a single or combinational therapy. Accompanying hepatotoxicity makes its use in elderly patients with pre-conditions, as obesity or other hepatopathies, difficult. Various hepatoprotective compounds like, L-carnitine, are discussed to ameliorate the induced hepatotoxicity. Methods: Here we aimed to establish a mouse model to study the effect of asparaginases (L-asparaginase and Oncaspar) and L-carnitine on Western-diet-induced hepatosteatosis in mice. Dose-escalation studies were performed to analyze asparaginases induced hepatotoxicity in C57BL/6 mice with normal or fatty livers. Subsequently, the effect of L-carnitine to improve the induced toxicity was tested. Results: Our results showed mild-to-moderate hepatotoxic effects while the Western-diet induced a higher degree of vacuolization and hepatocyte damage in liver tissue. Testing of L-carnitine in the established models did not show any protective effect on the toxicity or impairment of the efficacy of asparaginases. Conclusion: The here established models were able to demonstrate the asparaginase-induced hepatotoxic effects which were enhanced by the Western-diet. However, to test potential ameliorating drugs, the models might need some improvements.

SUBMITTER: Ali Mahmoud Assar M

PROVIDER: S-EPMC10366552 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Effects of asparaginases and L-carnitine on Western-diet-induced hepatosteatosis in mice.

Ali Mahmoud Assar Mona M Hüffel Martina M Afify Mamdouh M Weiskirchen Ralf R Eisert Albrecht A Tolba Rene R Steitz Julia J

F1000Research 20220201

<b>Background:</b> Asparaginases are common chemotherapeutic agents used for the treatment of acute lymphoblastic leukemia as a single or combinational therapy. Accompanying hepatotoxicity makes its use in elderly patients with pre-conditions, as obesity or other hepatopathies, difficult. Various hepatoprotective compounds like, L-carnitine, are discussed to ameliorate the induced hepatotoxicity. <b>Methods:</b> Here we aimed to establish a mouse model to study the effect of asparaginases (L-asp ...[more]

PMID: 37497390

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Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative.MethodsWe evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice.ResultsMice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content.ConclusionThese studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice.

Dataset Information

Effects of asparaginases and L-carnitine on Western-diet-induced hepatosteatosis in mice.

Publications

Effects of asparaginases and L-carnitine on Western-diet-induced hepatosteatosis in mice.

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