Caffeine attenuates the progression of liver fibrosis by inhibiting HSCs adhesion and activation.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25-30% of the population, and is the most common cause of elevated liver enzymes in Korea. NAFLD is a “hot potato” for pharmaceutical companies. Many clinical trials are underway to develop a first-in-class drug to treat NAFLD. However, there are several challenging issues regarding the diagnosis of NAFLD. Currently, liver biopsy is the gold standard method for the diagnosis of NAFLD and steatohepatitis. Ideally, globally recognized standards for histological diagnosis and methods to optimize observer agreement on biopsy interpretation should be developed. Liver biopsy is the best method rather than a perfect one. Recently, multi-parametric magnetic resonance imagery can estimate the amount of intrahepatic fat successfully and is widely used in clinical trials. But no diagnostic method can discriminate between steatohepatitis and simple steatosis. The other unresolved issue in regard to NAFLD is the absence of satisfactory treatment options. Vitamin E and obeticholic acid have shown protective effects in randomized controlled trials, but this drug has not been approved for use in Korea. This study will provide a description of diagnostic methods and treatments that are currently recommended for NAFLD.

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Background. We used high-fat (HF), high-fructose (HFr), and combination diets to create a dietary animal model of nonalcoholic fatty liver disease (NAFLD). Comparison of both clinical phenotypes has not been well defined. The purpose of this study was to compare histologic and metabolic characteristics between diets in an animal model of NAFLD. Methods. NAFLD was induced in rats by feeding them HF, HFr, and combination (HF + HFr) diets for 20 weeks. The degree of intrahepatic fat accumulation, inflammation, and oxidative stress was evaluated. Metabolic derangements were assessed by the oral glucose tolerance test and the intrahepatic insulin signal pathway. Results. Body weight gain and intrahepatic fat accumulation were more prominent in the HF feeding group than in the HFr group. The expressions of NOX-4 and TLR-4 were higher in the HF and HFr combination groups than in the HF-only group. Other intrahepatic inflammatory markers, MCP-1, TNF-α, and endoplasmic reticulum stress markers, were the highest in the HF + HFr combination group. Although intrahepatic fat deposition was less prominent in the HFr diet model, intrahepatic inflammation was noted. Conclusions. Intrahepatic inflammation and metabolic derangements were more prominent in the HF and HFr combination model than in the HF monodiet model.

Background and AimReceptor‐interacting serine/threonine kinase 3 and mixed lineage kinase domain‐like pseudokinase (MLKL) have gained attention as apoptosis alternate cell death signaling molecules. We aimed to evaluate the role of MLKL in non‐alcoholic fatty liver disease (NAFLD).MethodsHepatic tissue MLKL expression was compared between NAFLD patients and healthy controls. High‐fat diet was fed to wild‐type and MLKL‐knockout (KO) mice for 12 weeks. Brown adipose fat tissue was measured by [18F]‐fluorodeoxyglucose positron emission tomography. Energy expenditure was measured by indirect calorimetry. Anti‐MLKL effects were also evaluated in in vitro setting using U937 and HepG2 cells.ResultsHepatic tissue MLKL expression increased in NAFLD patients compared with healthy controls. MLKL expression increased according to the degree of steatosis, ballooning, and inflammation. High‐fat diet‐fed MLKL‐KO mice displayed decreased alanine aminotransferase, triglycerides, liver weight, NAFLD activity score (6.3 vs 3.5, P < 0.001), steatosis score (3.0 vs 1.8, P < 0.001), inflammation, and ballooning degeneration compared with wild‐type mice. SREBP1c, fatty acid synthase, and SCD‐1 expressions decreased in MLKL‐KO mice. Adipose tissue F4/80‐positive crown‐like structures were also reduced in MLKL‐KO mice. HepG2 cells treated with necrosulfonamide (an MLKL inhibitor) showed reduced Nile red staining and reduced SREBP1c and SCD‐1 expressions. Stimulation of necroptosis using lipopolysaccharide + caspase inhibitor (zVAD) increased CXCL1/2 expressions in U937 monocyte cells. Lipopolysaccharide + zVAD‐induced increased expressions of CXCL1/2 were reduced with necrosulfonamide treatment.ConclusionsMixed lineage kinase domain‐like pseudokinase inhibition has protective effects in non‐alcoholic steatohepatitis by decreasing hepatic de novo fat synthesis and chemokine (C‐X‐C motif) ligand expressions.