Didemnina B Mejora la Esteatosis Hepática, la Tolerancia a la Glucosa y los Lípidos en Sangre en la Obesidad de las Vías Implicadas en la Respuesta al Estrés Celular y el Equilibrio Energético en el Hígado...

 Abstract :

Inhibition of Eukaryotic Elongation Factor 1A1 (EEF1A1) With The Marine Compound Didemnin B Decreases Lipotoxic HepG2 cell Death In Vitro and Improves EarlyStage Non-Alcoholic Fatty Liver Disease (NAFLD) In Young Genetically Obese Mice .

 However, the Effects of Didemnin B on NAFLD in a Model of Long-Term Diet-Induced Obesity Are Not Known. 

We Investigated the Effects of Didemnin B on NAFLD severity and Metabolic Parameters in Western Diet-Induced Obese Mice, and on the Cell Types that Contribute to Liver Inflammation and Fibrosis in Vitro.

 Male 129S6 Mice were fed either standard chow or western diet for 26 weeks, followed by intervention with Didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. 

Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. 

Moreover, Didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a).

 In vitro, Didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. 

Thus, Didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. 

Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro.

 These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

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Conclusion :

NAFLD is a Growing Worldwide Epidemic for Which There Are No Approved Pharmacological Therapies.

 This, in Combination with a Scarcity of Non-Invasive diagnostic tools, allows Patients to Progress to end-stage Liver disease, at which point the sole Treatment option is Liver Transplantation.

 In the Present Study, We Show for the First Time that, in Western diet-Induced Obese Mice, Treatment with Didemnin B improves NAFLD Histopathology, Glucose Homeostasis, and Dyslipidemia.

 Moreover, in vitro, Didemnin B Preferentially Targets the Cell Types That Would Participate in NAFLD Progression. 

This Study Highlights the Potential of Partial EEF1A1 Inhibition As a Novel Pharmacological Strategy in The Treatment of NAFLD, For Which There Is a Critical Need.