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Objective Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. Methods Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1−/−) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. Results Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. Conclusions These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions., Highlights • Increases in cholesterol in NAFLD and NASH is a vexing problem. • PAR2 has been identified as a connecting hub between metabolism and fibrosis. • Severity of NAFLD and cholesterol correlate with hepatocyte PAR2 expression. • PAR2 suppresses reverse cholesterol transport and lipid breakdown in liver.

Highlights • Performance of MGB with a 200 cm bypassed limb in a morbidly obese female. • Presentation of anemia, low albumin, elevated LFT at 8th month despite good intake. • NAFLD activity score progressed from 2/8 to 7/8, leading to revisional surgery. • Rapid course of weight loss after BS and/or long bypassed limb could be responsible. • Bowel length measurement is recommended to avoid a short common intestinal channel., Introduction Mini-gastric bypass (MGB) is a popular bariatric procedure. Its effect on non-alcoholic fatty liver disease (NAFLD), however, has not yet been comprehensively studied. Presentation of case A 57 year-old non-alcoholic female with a body mass index of 42.8 kg/m2 underwent MGB without any incident. A concurrent liver biopsy showed an NAFLD activity score (NAS) of 2/8 without fibrosis. She presented at postoperative month eight with edema, vague abdominal pain, nausea, and vomiting and was hospitalized. Her BMI had dropped to 25.7 kg/m2. Her blood workup revealed mild anemia, mildly elevated liver enzymes, and hypoalbuminemia (2.5 g/dL). Liver ultrasound revealed grade-2 fatty liver. She received parenteral nutrition and intensive nutrient supplementation. Nevertheless, with regard to unsuccessful supportive measures and rising liver enzymes, revisional surgery −gastrogastrostomy- was performed. Her liver biopsy demonstrated a NAS of 7/8 at the time of revisional surgery. Her postoperative course was uneventful and she was discharged after one week. Discussion Bariatric surgery has shown favorable results regarding improvement of NAFLD in morbid obesity. This beneficial effect has been linked to the amount of weight loss. However, case reports have shown deteriorating liver function and NAFLD even after significant weight loss. They all have in common significant weight loss in a relatively short period of time. There may also be a connection between specific bariatric surgery procedures and this phenomenon. Conclusion Future studies comparing the effect of various bariatric procedures, including MGB, are necessary to help clinicians decide the optimal procedure for patients with this liver condition.

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts toward obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein., Highlights • Numerous non-invasive NAFLD biomarkers are developed but none is broadly applicable • OMICS enrich the understanding, diagnosis and treatment of NAFLD, NASH and fibrosis • Genomics and epigenomics pinpoint NAFLD polymorphisms and DNA methylation loci • Transcriptomics and proteomics prove the diagnostic value of miRNAs and peptides • Metabolomics, lipidomics and glycomics offer robust panels and therapeutic insight