The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

Unhealthy behaviours, including diet and physical activity, coupled with genetic predisposition, drive type 2 diabetes (T2D) occurrence and severity; the present review aims to summarise the most recent nutritional approaches in T2D, outlining unmet needs. Guidelines consistently suggest reducing energy intake to counteract the obesity epidemic, frequently resulting in sarcopenic obesity, a condition associated with poorer metabolic control and cardiovascular disease. Various dietary approaches have been proposed with largely similar results, with a preference for the Mediterranean diet and the best practice being the diet that patients feel confident of maintaining in the long term based on individual preferences. Patient adherence is indeed the pivotal factor for weight loss and long-term maintenance, requiring intensive lifestyle intervention. The consumption of nutritional supplements continues to increase even if international societies do not support their systematic use. Inositols and vitamin D supplementation, as well as micronutrients (zinc, chromium, magnesium) and pre/probiotics, result in modest improvement in insulin sensitivity, but their use is not systematically suggested. To reach the desired goals, patients should be actively involved in the collaborative development of a personalised meal plan associated with habitual physical activity, aiming at normal body weight and metabolic control.