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The antianginal ranolazine mitigates obesity-induced nonalcoholic fatty liver disease and increases hepatic pyruvate dehydrogenase activity
Rami Al Batran, … , Gopinath Sutendra, John R. Ussher
Rami Al Batran, … , Gopinath Sutendra, John R. Ussher
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e124643. https://doi.org/10.1172/jci.insight.124643.
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Research Article Hepatology Metabolism

The antianginal ranolazine mitigates obesity-induced nonalcoholic fatty liver disease and increases hepatic pyruvate dehydrogenase activity

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Abstract

Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine’s actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.

Authors

Rami Al Batran, Keshav Gopal, Hanin Aburasayn, Amina Eshreif, Malak Almutairi, Amanda A. Greenwell, Scott A. Campbell, Bruno Saleme, Emily A. Court, Farah Eaton, Peter E. Light, Gopinath Sutendra, John R. Ussher

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Figure 6

Ranolazine-mediated reductions in body weight are not required for ranolazine’s salutary actions on NAFLD and dysglycemia.

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Ranolazine-mediated reductions in body weight are not required for ranol...
(A) Pyruvate tolerance and associated AUC. (B) Liver TAG content and (C) body weights in obese mice treated acutely with either vehicle control (VC) or ranolazine (Ran) (n = 4). (D) Pyruvate tolerance and associated AUC. (E) Liver TAG content and (F) body weights in obese mice treated with either VC or Ran for 1 week (n = 5–6). Values represent means ± SEM. Differences were determined with an unpaired, 2-tailed Student’s t test or a 2-way ANOVA, followed by a Bonferroni post hoc analysis. *P < 0.05, significantly different from VC-treated counterpart.

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