Purpose Fructose is highly lipogenic, and its unhindered ingestion by children and adolescents is understood to induce hypertriglyceridemia and non-alcoholic fatty liver disease (ped-NAFLD) that is till date managed symptomatically or surgically. The aim of the present study was to investigate the potential of hydroethanolic extract of leaves of Guava (PG-HM) to suppress the alterations in the hepatic molecular signals due to unrestricted fructose (15%) drinking by growing rats. Methods Weaned rats (4 weeks old) in control groups had ad libitum access to fructose drinking solution (15%) for four (4FDR) or eight (8FDR) weeks, ie, till puberty or early adulthood, respectively, while treatment groups (4PGR, 8PGR) additionally received PG-HM (500 mg/kg, po). Results The PG-HM suppressed ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I–V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/ de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). Parri passu , the insulin sensitizing effect of PG-HM and its ethyl acetate fraction (PG-EA) was elucidated using HepG2 cells grown in media enhanced with fructose. Further, in murine hepatocytes cultured in fructose-rich media, PG-HM (35 µg mL-1) outperformed Pioglitazone (15 µM) and Metformin (5 mM), to suppress hepatic insulin resistance. Conclusion This study established that hydroethanolic extract of leaves of Guava (PG-HM) has potential to suppress hepatic metabolic alteration for the management of the pediatric NAFLD.

To develop hydroethanolic extract of leaves of Psidium guajava L. (Myrtaceae), identify novel target and lead compound for pediatric non alcoholic fatty liver disease (ped-NAFLD). Hydroethanolic extract (PG-HM) and sequential fractions of locally collected leaves of P.guajava were prepared and standardized for quercetin content using LC-MS/MS. The effect of PG-HM on markers of ped-NAFLD in weaned rats with unrestricted access to liquid fructose (15%) till puberty and early adulthood, was evaluated. The PG-HM was investigated using 1) HepG2 cells grown in fructose containing medium for intercellular signalling, 2) isolated murine hepatocytes for mitochondrial effects, 3) jejunum isolated from fructose drinking rats for effect on ex vivo fructose transport, 4) molecular dynamics for in silico binding of quercetin with GLUT5, 5) normal rats for oral pharmacokinetics. The quercetin content in PG-HM was 3630.66 ± 17.61 ng ml-1 and the Cmax and Tmax were 140.527 ± 5.718 ng ml-1 and 0.75 ± 0.079 h, respectively. The PG-HM mitigated ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I-V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). For the first time, the PG-HM is reported to reduce and delay the fructose transport across jejunum that may be implicated to the binding of quercetin with GLUT5. For prevention and treatment of ped-NAFLD, the PG-HM, GLUT5 and quercetin are evidenced as dietary supplement, drug target and lead compound, respectively.