A theoretical study of lipid accumulation in the liver—implications for nonalcoholic fatty liver disease

A hallmark of the nonalcoholic fatty liver disease is the accumulation of lipids. We developed a mathematical model of the hepatic lipid dynamics to simulate the fate of fatty acids in hepatocytes. Our model involves fatty acid uptake, lipid oxidation, and lipid export. It takes into account that storage of triacylglycerol within hepatocytes leads to cell enlargement reducing the sinusoids radius and impairing hepatic microcirculation. Thus oxygen supply is reduced, which impairs lipid oxidation. The analysis of our model revealed a bistable behavior (two stable steady states) of the system, in agreement with histological observations showing distinct areas of lipid accumulation in lobules. The first (healthy) state is characterized by intact lipid oxidation and a low amount of stored lipids. The second state in our model may correspond to the steatotic cell; it is marked by a high amount of stored lipids and a reduced lipid oxidation caused by impaired oxygen supply. Our model stresses the role of insufficient oxygen supply for the development of steatosis. We discuss implications of our results in regard to the experimental design aimed at exploring lipid metabolism reactions under steatotic conditions. Moreover, the model helps to understand the reversibility of lipid accumulation and predicts the reversible switch to show hysteresis. The system can switch from the steatotic state back to the healthy state by reduction of fatty acid uptake below the threshold at which steatosis started. The reversibility corresponds to the observation that caloric restriction can reduce the lipid content in the liver.     

Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD

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The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common underlying causes of chronic liver injury. They are associated with a wide spectrum of hepatic disorders including basic steatosis, steatohepatitis, and cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD and NASH are still unknown. This review describes the roles of oxidative stress and inflammatory responses in the pathogenesis of NAFLD and its progression to NASH.     

Fibroblast Growth Factor-5 Participates in the Progression of Hepatic Fibrosis

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation, and fibrosis and is believed to develop via a “two-hit process”; however, its pathophysiology remains unclear. Fibroblast growth factors (FGFs) are heparin-binding polypeptides with diverse biological activities in many developmental and metabolic processes. In particular, FGF5 is associated with high blood pressure. We investigated the function of FGF5 in vivo using spontaneously Fgf5 null mice and explored the role of diet in the development of NASH. Mice fed a high-fat diet gained little weight and had higher serum alanine transaminase, aspartate amino transferase, and non–high-density lipoprotein-cholesterol levels. Liver histology indicated marked inflammation, focal necrosis, fat deposition, and fibrosis, similar to the characteristics of NASH. FGF5 and a high-fat diet play significant roles in the pathophysiology of hepatic fibrosis and Fgf5 null mice may provide a suitable model for liver fibrosis or NASH.     

鸢尾素改善肝脏脂质代谢紊乱减轻非酒精性脂肪性肝病的研究现状

肝脏大量脂质蓄积是非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）的重要病理特征。肝脏脂质摄取、脂质从头合成、脂肪酸氧化分解和脂质分泌输出这4个环节间的失衡是造成肝脏脂质蓄积的重要原因。运动具有改善脂质代谢,缓解NAFLD发展的作用,但其机制复杂尚未完全阐明。肌肉不仅是运动器官,还是重要的内分泌器官,一系列介导运动促进健康效应的内分泌因子主要由肌肉产生。鸢尾素（Irisin）是主要由肌肉分泌的内分泌因子,其合成和分泌受运动调节,可靶向机体多种器官组织,发挥改善NAFLD等肥胖相关慢性代谢性疾病的作用。Irisin改善NAFLD的效应与其对脂质代谢的积极调控作用密不可分。本文阐述了运动调控Irisin合成与分泌的可能机制,并对Irisin改善上述4个肝脏脂质代谢的重要环节、减轻NAFLD的研究进展进行了总结,同时提出其中尚需进一步明确的问题,以期更好地理解Irisin介导运动在NAFLD等代谢疾病中的作用。     

体内肉碱来源及其对脂类代谢的影响

肉碱是体内一种有多种生理功能的氨基酸类物质,其在脂类代谢过程中有重要的调节作用,近年来在甘油三脂血症、肾透析患者的脂代谢障碍的辅助治疗中取得了较好疗效。本文就肉碱的来源和对脂类代谢的影响进行了讨论。     

Progesterone receptor membrane component 1/Sigma-2 receptor associates with MAP1LC3B and promotes autophagy

Autophagy resembles a recycling process in which proteins, organelles, or regions of the cytoplasm are enveloped and degraded. We have found that two of the central autophagy proteins, MAP1LC3 (microtubule-associated protein 1 light chain 3, also described as LC3) and UVRAG (UV radiation resistance associated/UV radiation associated gene), complex with PGRMC1/S2R (progesterone receptor membrane component 1, also known as sigma-2 receptor). PGRMC1 is a cytochrome that is induced in cancer and is essential for tumor formation, invasion, and metastasis. Autophagy contributes to the turnover of long-lived and/or ubiquitinated proteins and the clearance of damaged organelles, and we have shown that PGRMC1 promotes both processes. Inhibition of PGRMC1 by RNAi or small molecule inhibitors causes autophagy substrates to increase and aberrant mitochondria to accumulate. We propose that this disruption of autophagy upon PGRMC1 inhibition increases AMPK activation, elevating the levels of TSC1 (tuberous sclerosis complex) and TSC2 and inactivating MTOR and RPS6KB/p70S6K, causing cleaved MAP1LC3B levels to increase. Thus, PGRMC1 binds to key components of the autophagy machinery and is required for the degradative activity of autophagy.