Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid β-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment.

Background: Obesity is a major global public health issue with no fully satisfactory solutions. Most nutritional interventions rely on caloric restriction, with varying degrees of success. Very low-calorie ketogenic diets (VLCKD) have demonstrated rapid and sustained weight loss by inducing ketone bodies through lipolysis, reducing appetite, and preserving lean mass while maintaining metabolic health. Methods: A prospective clinical study analyzed sociodemographic, anthropometric, and adherence data from 7775 patients undergoing a multidisciplinary nutritional single-arm intervention based on a commercial weight-loss program. This method, using protein preparations with a specific balanced nutritional profile, aimed to identify key predictors of weight-loss success and classify population phenotypes with shared baseline characteristics and weight-loss patterns to optimize treatment personalization. Results: Statistical and machine learning analyses revealed that male gender (−9.2 kg vs. −5.9 kg) and higher initial body weight (−8.9 kg vs. −4.0 kg) strongly predict greater weight loss on a VLCKD, while age has a lesser impact. Two distinct population clusters emerged, differing in age, sex, follow-up duration, and medical visits, demonstrating unique weight-loss success patterns. These clusters help define individualized strategies for optimizing outcomes. Conclusions: These findings translationally support associations with the efficacy of a multidisciplinary VLCK weight-loss program and highlight predictors of success. Recognizing variables such as sex, age, and initial weight enhances the potential for a precision-based approach in obesity management, enabling more tailored and effective treatments for diverse patient profiles and prescribe weight loss personalized recommendations.