L-theanine Prevents Progression of Nonalcoholichepatic Steatosis by Regulating Hepatocyte Lipid Metabolic Pathways via the CaMKKβ-AMPK Signaling Pathway

Background: L-theanine, a non-protein amino acid found principally in the green tea, has been previously shown to possess potent anti-obesity property and hepatoprotective effect. Herein, we investigated the effects of L-theanine on alleviating nonalcoholic hepatic steatosis in vitro and in vivo, and explored the underlying molecular mechanism. Methods: In vitro, HepG2 and AML12 cells were treated with 500 μM oleic acid (OA) or treated with OA accompanied by L-theanine. In vivo, C57BL/6J mice were fed with normal control diet (NCD), high‐fat diet (HFD), or HFD along with L-theanine for 16 weeks. The levels of TG, accumulation of lipid droplets and the expression of genes related to hepatocyte lipid metabolic pathways were detected in vitro and in vivo.Results: Our data indicated that, in vivo, L-theanine significantly reduced body weight, hepatic steatosis, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), TG and LDL cholesterol (LDL-C) in HFD-induced Non-alcoholic fatty liver disease (NAFLD) mice. In vitro, L-theanine also significantly alleviated OA induced hepatocytes steatosis. Mechanic studies showed that L-theanine significantly inhibited the nucleus translocation of sterol regulatory element binding protein 1c (SREBP-1c) through AMPK-mTOR signaling pathway, thereby contributing to the reduction of fatty acid synthesis. We also identified that L-theanine enhanced fatty acid β-oxidation by increasing the expression of peroxisome proliferator–activated receptor α (PPARα) and carnitine palmitoyltransferase-1 A (CPT1A) through AMP-activated protein kinase (AMPK). Furthermore, our study indicated that L-theanine can active AMPK via its upstream kinase Calmodulin-dependent protein kinase kinase-β (CaMKKβ). Conclusions: Taken together, our findings suggest that L-theanine alleviates nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.

Considerations regarding liver current pathology

This work presents reasoning about liver pathology. Liver pathology is an area of interest due to the growing number of medical cases worldwide. The factors associated with the appearance of this pathology are those that relate to individual lifestyle. Liver pathology studies are performed up to the biomolecular level, involving cytochrome P450 2E1 (CYP2E1). With a normal liver, subject to aging and the aforementioned risk factors, there are changes in liver structure, which often can lead to changes arising from nonalcoholic hepatic steatosis (NASH). Under certain circumstances this degenerates into chronic hepatitis, which often goes undiagnosed and this can lead to liver cirrhosis. Due to gradual changes in the liver, medical interventions are often delayed. Importantly, structural analysis of microscopically processed liver fragments will reveal changes in all structural elements of the liver, from lipid loading in hepatic steatosis to inflammatory, necrotic, destructive, fibrotic changes in liver cirrhosis, including somewhat similar changes in types of chronic hepatitis. The presented images and the described structural changes in the liver are an important criterion for liver damage, including preclinical pathology.

Mechanism of Huo-Xue-Qu-Yu Formula in Treating Nonalcoholic Hepatic Steatosis by Regulating Lipid Metabolism and Oxidative Stress in Rats

Huo-Xue-Qu-Yu formula (HXQYF) is a prescription consisting of Ginkgo biloba leaf and Paeonia lactiflora Pall. for treating hyperlipidemia and NAFLD in China. Here, we investigated the hepatic and renal function, oxidative stress and lipid metabolism, and potential mechanisms of HXQYF on nonalcoholic fatty liver disease (NAFLD) rat models. NAFLD rat models were induced with high-fat diet (HFD) and 10% fructose water for 18 weeks and orally administered with or without HXQYF simultaneously. The results showed that HXQYF (22.5, 45, 90 mg/kg) significantly improved blood lipid levels via reducing serum TC, TG, LDL-C, and APOB values and elevating HDL-C and APOA1 levels in NAFLD rats. The higher levels of ALT, AST, CR, and BUN in serum induced by HFD were reduced by HXQYF. HE staining showed that HXQYF (90 mg/kg) reduced the accumulation of fat droplets and alleviated inflammatory response in liver cells. Three doses of HXQYF exhibited notable antioxidant effects by elevating SOD, GSH, and CAT activities and decreasing MDA and OH-1 levels in the liver. Furthermore, abnormal lipid metabolism caused by HFD was alleviated by HXQYF, which was associated with the upregulation of PPAR-α, AdipoR2, and CPT1 mRNAs as well as the downregulation of CYP2E1 and SREBP-1c mRNAs in liver tissue. In conclusion, our work verified that HXQYF could reduce the degree of hepatic steatosis, suppress oxidative stress, and attenuate lipid metabolism, thus preventing NAFLD.

Role of vascular endothelial growth factor in the pathogenesis of hepatic steatosis and dyslipidemia

Цель исследования - изучение роли васкулоэндотелиального фактора роста в патогенезе неалкогольного стеатоза печени и дислипидемии при метаболическом синдроме. Методика. Обследовано 35 пациентов с неалкогольным стеатозом печени, в том числе 22 женщины и 13 мужчин. Группу контроля составили 12 сопоставимых по полу и возрасту лиц без патологии печени и признаков метаболического синдрома. Наличие жирового гепатоза подтверждали методом ультразвукового исследования. У пациентов с патологией печени рассчитывали индексы-предикторы стеатоза: Fatty Liver Index (FLI) и Hepatic Steatosis Index (HSI). У всех участников исследования определяли уровни провоспалительных цитокинов и васкулоэндотелиального фактора роста (ВЭФР), оценивали также липидный спектр крови и функциональные печеночные пробы. Результаты. У пациентов со стеатозом печени наблюдалось значимое увеличение уровней провоспалительных цитокинов, ВЭФР, общего холестерина и липопротеинов низкой и очень низкой плотности. Индекс атерогенности также был значимо выше, чем в контрольной группе. Концентрация ВЭФР положительно коррелировала с показателями окружности талии, тимоловой пробы, уровнями общего холестерина, липопротеинов низкой плотности и индексом атерогенности. Чувствительность FLI составила 91,4%, HSI - 97,1%. При этом, значения FLI и HSI значимо коррелировали с уровнем ВЭФР. Заключение. Полученные данные позволяют предположить, что ВЭФР, один из основных маркеров эндотелиальной дисфункции, может играть немаловажную роль в патогенезе неалкогольного стеатоза печени и дислипидемии у пациентов с метаболическомим синдромом The aim of the study was to assess the role of vascular endothelial growth factor (VEGF) in the pathogenesis of nonalcoholic hepatic steatosis and dyslipidemia in patients with signs of metabolic syndrome. Methods. 35 patients with nonalcoholic fatty liver disease, including 22 women and 13 men, were evaluated. The sex- and age-matched control group consisted of 12 people without liver pathology and metabolic syndrome criteria. Presence of hepatic steatosis was confirmed by an ultrasound examination. The Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI) were calculated for patients with hepatic steatosis. Concentrations of proinflammatory cytokines and VEGF were measured for all participants. Also, blood biochemistry, including the lipid profile and liver function tests, was analyzed. Results. In patients with hepatic steatosis, levels of proinflammatory cytokines and VEGF were significantly increased. Also, concentrations of total cholesterol, low-density lipoproteins, and very low-density lipoproteins were higher in patients with the liver pathology than in the control group. Atherogenic coefficient was increased in hepatic steatosis. Significant correlations were observed between VEGF and waist circumference, thymol test, total cholesterol, low-density lipoproteins, very low-density lipoproteins, and atherogenic coefficient. Sensitivity of FLI and HIS was 91.4% and 97.1%, respectively. Also, FLI significantly correlated with HSI and VEGF level. Conclusion. The study suggested that VEGF, of the main markers of endothelial dysfunction, plays an important role in the pathogenesis of nonalcoholic hepatic steatosis and dyslipidemia in patients with signs of metabolic syndrome.