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

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

doi:10.1172/jci.insight.124643

Cited by 14 publications

(26 citation statements)

References 36 publications

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“…For example, a recent study conducted on obese mice demonstrated that ranolazine mitigates hepatic steatosis. 19 This beneficial action of ranolazine as a metabolic modulator is probably related to increased hepatic PDH activity, the rate-limiting enzyme of glucose oxidation, 16 consistent with past studies demonstrating that PDH is a novel target for ameliorating NAFLD. 17,18 Therefore, for the first time, we aimed to investigate the impact of ranolazine on the activities of both transaminase in established patients with CAD with NAFLD.…”

Section: Discussionsupporting

confidence: 72%

“…Ranolazine’s actions on hepatic PDH activity may be directly mediated, as ranolazine increases the amount of active dephosphorylated PDH and stimulates glucose oxidation at the expense of fatty acid oxidation. 15,19 The term NAFLD covers a broad spectrum of pathology ranging from simple steatosis to steatosis with evidence of hepatocellular inflammation and injury, and previous studies have indicated that inflammatory processes throughout the series of events leading to hepatotoxicity are critical pathogenic factors. 28–30 Advanced stages of NAFLD related to inflammation are more deleterious to coronary, carotid, and peripheral arteries and are related to an adverse outcome.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 Ranolazine also mitigates hepatic steatosis in obese mice. 19 Therefore, we investigated the action of ranolazine on liver tests in patients with CAD and NAFLD, by measuring serum transaminase activities.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Impact of Ranolazine Treatment on Liver Function Tests in Patients With Coronary Heart Disease and Nonalcoholic Fatty Liver Disease

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology in the developed world. Nonalcoholic fatty liver disease is associated with a higher risk of cardiovascular disease. We investigated the impact of ranolazine on liver tests in patients with NAFLD and coronary artery disease (CAD). Patients who had established CAD and NAFLD (as assessed by raised serum transaminase activity, sonographic criteria, and the absence of any other obvious liver disease) were allocated to “on ranolazine” (n = 40) or “not on ranolazine” (n = 35) groups. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in all patients at baseline and at the end of the study. After 6 months of ranolazine treatment, both ALT and AST activities were significantly lower in patients in the “on ranolazine” group compared with “not on ranolazine” patients (change from baseline: ALT, −11.0 ± 1.7 IU/L, P < .001; AST, −5.2 ± 1.9 IU/L, P =.009). In conclusion, the present study showed that treatment with ranolazine for 6 months led to a significant reduction in the activities of both serum aminotransferases in patients with stable CAD and NAFLD.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Evaluation of the Impact of Ranolazine Treatment on Liver Function Tests in Patients With Coronary Heart Disease and Nonalcoholic Fatty Liver Disease

et al. 2021

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“…A 6 h fast was chosen for the ITT, as lean C57BL/6J mice are highly insulin sensitive and may become hypoglycaemic during an ITT following an overnight fast, due to their baseline glucose levels decreasing to ∼4 m m . Blood glucose was measured at 0, 15, 30, 60, 90 and 120 min post‐glucose or insulin administration from mouse tail whole‐blood using the Contour Next blood glucose monitoring system (Bayer, Leverkusen, Germany) as previously described (Al Batran et al., , ). In addition, blood samples were collected in tubes containing the anticoagulant agent (EDTA) at 0 and 30 min post‐glucose administration, in order to measure plasma insulin levels via use of a commercially available kit (Alpco Diagnostics, Salem, NH, USA) as previously described (Al Batran et al., ).…”

Section: Methodsmentioning

confidence: 99%

l‐Citrulline supplementation improves glucose and exercise tolerance in obese male mice

Eshreif

Batran

Jamieson

et al. 2020

Experimental Physiology

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L-Citrulline is an organic -amino acid that has been shown to have a number of salutary actions on whole-body physiology, including reducing muscle wasting and augmenting exercise and muscle performance. The latter has been suggested to arise from elevations in mitochondrial function.Because enhancing mitochondrial function has been proposed as a novel strategy to mitigate insulin resistance, our goal was to determine whether supplementation with L-citrulline could also improve glycaemia in an experimental mouse model of obesity. We hypothesized that L-citrulline treatment would improve glycaemia in obese mice, and this would be associated with elevations in skeletal muscle mitochondrial function. Ten-week-old C57BL/6J mice were fed either a lowfat (10% kcal from lard) or a high-fat (60% kcal from lard) diet, while receiving drinking water supplemented with either vehicle or L-citrulline (0.6 g l −1 ) for 15 weeks. Glucose homeostasis was assessed via glucose/insulin tolerance testing, while in vivo metabolism was assessed via indirect calorimetry, and forced exercise treadmill testing was utilized to assess endurance. As expected, obese mice supplemented with L-citrulline exhibited an increase in exercise capacity, which was associated with an improvement in glucose tolerance. Consistent with augmented mitochondrial function, we observed an increase in whole body oxygen consumption rates in obese mice supplemented with L-citrulline. Surprisingly, L-citrulline supplementation worsened insulin tolerance and reduced insulin signalling in obese mice. Taken together, although L-citrulline supplementation improves both glucose tolerance and exercise capacity in obese mice, caution must be applied with its broad use as a nutraceutical due to a potential deterioration of insulin sensitivity. K E Y W O R D Sexercise capacity, glucose homeostasis, L-citrulline, mitochondrial function, obesity 1 wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:270-281.

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“…8 Ranolazine (a second-line antianginal drug) is among several drugs evaluated for the management of NAFLD. 9 An experimental study in mice found that ranolazine administration reversed obesity-induced glucose intolerance and decreased body weight as well as hepatic steatosis. 9 These findings suggested that ranolazine may reverse NAFLD histopathological findings and potentially reduce transaminase activity.…”

mentioning

confidence: 99%

The Impact of Ranolazine Treatment on Liver Tests in Patients With Coronary Artery Disease and Nonalcoholic Fatty Liver Disease

et al. 2021

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

Cited by 14 publications

References 36 publications

Evaluation of the Impact of Ranolazine Treatment on Liver Function Tests in Patients With Coronary Heart Disease and Nonalcoholic Fatty Liver Disease

Evaluation of the Impact of Ranolazine Treatment on Liver Function Tests in Patients With Coronary Heart Disease and Nonalcoholic Fatty Liver Disease

l‐Citrulline supplementation improves glucose and exercise tolerance in obese male mice

The Impact of Ranolazine Treatment on Liver Tests in Patients With Coronary Artery Disease and Nonalcoholic Fatty Liver Disease

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