Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor antidepressant, has been shown to increase hepatic lipid accumulation, a key factor in the development of non-alcoholic fatty liver disease. Interestingly, fluoxetine has also been reported to increase peripheral serotonin synthesis. As emerging evidence suggests that serotonin may be involved in the development of non-alcoholic fatty liver disease we sought to determine if fluoxetine-induced hepatic lipid accumulation is mediated via altered serotonin production. Fluoxetine treatment increased lipid accumulation in association with increased mRNA expression of tryptophan hydroxylase 1 (<i>Tph1, serotonin biosynthetic enzyme) and intracellular serotonin content. Serotonin alone had a similar effect to increase lipid accumulation. Moreover, blocking serotonin synthesis reversed the fluoxetine-induced increases in lipid accumulation. Collectively, these data suggest that fluoxetine induced lipid accumulation can be mediated, in part, by elevated serotonin production. These results suggest a potential therapeutic target to ameliorate the adverse metabolic effects of fluoxetine exposure.

Download Full-text

Bromelain Confers Protection Against the Non-Alcoholic Fatty Liver Disease in Male C57BL/6 Mice

Nutrients ◽

10.3390/nu12051458 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1458

Author(s):

Po-An Hu ◽

Chia-Hui Chen ◽

Bei-Chia Guo ◽

Yu Ru Kou ◽

Tzong-Shyuan Lee

Keyword(s):

Fatty Acids ◽

Liver Disease ◽

Fatty Liver ◽

Total Cholesterol ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Alcoholic Fatty Liver Disease

We aimed to investigate the effect of bromelain, the extract from stems of pineapples on the high-fat diet (HFD)-induced deregulation of hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD), and its underlying mechanism in mice. Mice were daily administrated with HFD with or without bromelain (20 mg/kg) for 12 weeks, and we found that bromelain decreased the HFD-induced increase in body weight by ~30%, organ weight by ~20% in liver weight and ~40% in white adipose tissue weight. Additionally, bromelain attenuated HFD-induced hyperlipidemia by decreasing the serum level of total cholesterol by ~15% and triglycerides level by ~25% in mice. Moreover, hepatic lipid accumulation, particularly that of total cholesterol, free cholesterol, triglycerides, fatty acids, and glycerol, was decreased by 15–30% with bromelain treatment. Mechanistically, these beneficial effects of bromelain on HFD-induced hyperlipidemia and hepatic lipid accumulation may be attributed to the decreased fatty acid uptake and cholesteryl ester synthesis and the increased lipoprotein internalization, bile acid metabolism, cholesterol clearance, the assembly and secretion of very low-density lipoprotein, and the β-oxidation of fatty acids by regulating the protein expression involved in the above mentioned hepatic metabolic pathways. Collectively, these findings suggest that bromelain has therapeutic value for treating NAFLD and metabolic diseases.

Download Full-text

Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04269-0 ◽

2021 ◽

Author(s):

Min-Jie Hu ◽

Mei Long ◽

Rong-Juan Dai

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Lncrna Neat1 ◽

Alcoholic Fatty Liver Disease

Download Full-text

Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease

Cells ◽

10.3390/cells9102244 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2244

Author(s):

Martijn R. Molenaar ◽

Louis C. Penning ◽

J. Bernd Helms

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Hepatic Fibrosis ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Stellate Cells ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid Accumulation

Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

Download Full-text

Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease

Experimental and Therapeutic Medicine ◽

10.3892/etm.2011.328 ◽

2011 ◽

Vol 2 (6) ◽

pp. 1077-1081 ◽

Cited By ~ 50

Author(s):

NOBITO HIGUCHI ◽

MASAKI KATO ◽

MASATAKE TANAKA ◽

MASAYUKI MIYAZAKI ◽

SHINICHIRO TAKAO ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Mrna Expression ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid Accumulation ◽

Alcoholic Fatty Liver Disease ◽

Mrna Expression Levels

Download Full-text

Apigenin Alleviates Non-Alcoholic Fatty Liver Disease by Downregulating the NLRP3/NF-κB Signaling Pathway in Mice

10.21203/rs.3.rs-885611/v1 ◽

2021 ◽

Author(s):

Zheng Lu ◽

Lu Liu ◽

Shunxin Zhao ◽

Jiangtao Zhao ◽

Sujun Li

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Signaling Pathway ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Abstract Background: Apigenin, a flavone found in several plant foods with various biological properties including anti-inflammatory and other abilities, alleviated non-alcohol fatty liver disease (NAFLD) induced by a high fat diet (HFD) in mice. However, the mechanisms underlying this protection of inflammation and NAFLD has not been known clearly. Methods: Low density lipoprotein receptor-deficient (Ldlr-/-) mice were fed with HFD diet to induce NAFLD model and were treated with apigenin (50 mg/kg/day) for eight weeks. Hepatic lipid accumulation and inflammation in the livers were analyzed and quantified. In vitro experiments, HepG2 cells were stimulated by LPS plus oleic acid (OA) in the absence of presence of apigenin (50μM). Lipid accumulation and the effect of apigenin on NLRP3/NF-κB signaling pathway was investigated.Results: Apigenin administration reduce the weight, plasma lipid levels in Ldlr-/- mice when fed an HFD. Apigenin (50 mg/kg/day) treated mice displayed reduced hepatic lipid accumulation and inflammation in the livers of mice given the HFD diet. Treating the HepG2 cells with apigenin reduced lipid accumulation. And, apigenin also inhibited activation of NLRP3/NF-κB signaling pathway stimulated by OA together with LPS. Conclusions: Our results indicated that apigenin supplementation prevented NAFLD via down-regulating the NLRP3/NF-κB signaling pathway in mice, and suggested apigenin might be a potential therapeutic agent for the prevention of NAFLD.

Download Full-text

Lingonberry Improves Non-Alcoholic Fatty Liver Disease by Reducing Hepatic Lipid Accumulation, Oxidative Stress and Inflammatory Response

Antioxidants ◽

10.3390/antiox10040565 ◽

2021 ◽

Vol 10 (4) ◽

pp. 565

Author(s):

Susara Madduma Hewage ◽

Suvira Prashar ◽

Karmin O ◽

Yaw L. Siow

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Liver Injury ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Inflammatory Cytokine ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally and there is a pressing need for effective treatment. Lipotoxicity and oxidative stress are the important mediators in NAFLD pathogenesis. Lingonberry (Vaccinium vitis-idaea L.) is rich in anthocyanins that have antioxidant and anti-inflammatory properties. The present study investigated the effect of lingonberry supplementation on liver injury in C57BL/6J male mice fed a high-fat diet (HFD) for 12 weeks. Mice fed HFD displayed liver injury with steatosis, increased lipid peroxidation and inflammatory cytokine expression in the liver as compared to mice fed a control diet. Lingonberry supplementation for 12 weeks alleviated HFD-induced liver injury, attenuated hepatic lipid accumulation, and inflammatory cytokine expression. Lingonberry supplementation inhibited the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and acetyl-CoA carboxylase-1 (AAC-1) as well as activated AMP-activated protein kinase (AMPK) in the liver. It also decreased HFD-induced hepatic oxidative stress and aggregation of inflammatory foci. This was associated with a restoration of nuclear factor erythroid 2–related factor 2 (Nrf2) and glutathione level in the liver. These results suggest that lingonberry supplementation can protect against HFD-induced liver injury partly through attenuation of hepatic lipid accumulation, oxidative stress, and inflammatory response.

Download Full-text

How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

Hepatology International ◽

10.1007/s12072-020-10121-2 ◽

2021 ◽

Vol 15 (1) ◽

pp. 21-35

Author(s):

Yana Geng ◽

Klaas Nico Faber ◽

Vincent E. de Meijer ◽

Hans Blokzijl ◽

Han Moshage

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Lipid Uptake ◽

Cellular Mechanisms ◽

Alcoholic Fatty Liver ◽

Lipid Species ◽

Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

Download Full-text