Calcitriol and candesartan mitigate monosodium glutamate-exacerbated metabolic syndrome and MASLD/MASH in rats: modulation of GLuR5/Ketohexokinase/FoxO1 axis.

The widespread consumption of monosodium glutamate (MSG) is linked to serious health threats which would be magnified when accompanied by high-fat/high-sugar diets. This study investigated the metabolic and hepatic perturbations of adding MSG to high fat/fructose diet in adult male rats and the possible ameliorative effects of calcitriol, and candesartan. Rats were fed high-fat/fructose diet plus sodium chloride (FF/NaCl) or MSG (FF/MSG) for 18 weeks, and were treated with either drug daily for the last 10 weeks. MSG exacerbated dyslipidemia, glucose intolerance, hypertension, and hepatic expression of mGLuR5 and ketohexoknase compared to NaCl. Both FF/NaCl and FF/MSG impaired hepatic insulin signaling biomarkers IRS-1 and Akt but MSG enhanced FoxO1 expression compared to NaCl. Furthermore, MSG exacerbated MASH hallmarks; steatosis, inflammation, and fibrosis. Both drugs mitigated most of the FF/MSG-induced metabolic and hepatic manifestations by downregulating mGLuR5, hetohexokinase, and FoxO1, beside their antioxidant, antiinflammatory, and antifibrotic effects. Calcitriol, and candesartan protect against MSG-induced hepatic derangements through downregulation of hepatic mGluR5, KHK, and FoxO1 expression in addition to their well-known anti-inflammatory and antifibrotic effects.