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

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA), triglyceride (TG), total cholesterol (TC), ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR) value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP)-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS), HMG-CoA reductase (HMGCR) and acetyl-Coenzyme A carboxylase (ACCα). In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing ClC-2 may be an attractive therapeutic strategy for the treatment of NAFLD.

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

Cellular and Molecular Life Sciences ◽

10.1007/s00018-018-2860-6 ◽

2018 ◽

Vol 75 (18) ◽

pp. 3313-3327 ◽

Cited By ~ 143

Author(s):

David Højland Ipsen ◽

Jens Lykkesfeldt ◽

Pernille Tveden-Nyborg

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Alcoholic Fatty Liver Disease

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Fluoxetine-induced Hepatic Lipid Accumulation is Linked to Elevated Serotonin Production

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0721 ◽

2021 ◽

Author(s):

Ahmed Ayyash ◽

Alison C Holloway

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Metabolic Effects ◽

Serotonin Synthesis ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

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.

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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.

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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

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Non-Alcoholic Fatty Liver Disease in Overweight Children and its Relationship with Retinol Serum Levels

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.78.1.27 ◽

2008 ◽

Vol 78 (1) ◽

pp. 27-32 ◽

Cited By ~ 15

Author(s):

Suano de Souza ◽

Silverio Amancio ◽

Saccardo Sarni ◽

Sacchi Pitta ◽

Fernandes ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Profile ◽

Fatty Liver Disease ◽

Thiobarbituric Acid ◽

Serum Levels ◽

Control Group ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Objectives: To evaluate the frequency of non-alcoholic fatty liver disease, the retinol serum levels, lipid profile, and insulin resistance in overweight/obese children. To relate these biochemical variables with the risk of this disease in the population studied. Methods: The study was cross-sectional and prospective, with 46 overweight/obese school children (28 female, 18 male; mean age 8.6 years). The control group consisted of 45 children, paired by age and gender. Hepatic steatosis, evaluated by ultrasound, was classified as normal, mild, moderate, or severe. Also evaluated were serum retinol levels; thiobarbituric acid reactive substances; lipid profile; and fasting glucose and serum insulin levels, used for the calculation of the Homeostasis Model Assessment. Results: Hepatic ultrasound alterations were found in 56.5% and 48,9% of the overweight/obese and control group children, respectively. Presence of obesity was associated with high levels of triglycerides (OR = 4.6; P = 0.002). In the studied children, the risk of steatosis was related to a trend to a higher percentage of retinol inadequacy (OR = 2.8; p = 0.051); there was no association with thiobarbituric acid reactive substances, lipid profile, or insulin resistance. Conclusions: The high frequency of non-alcoholic fatty liver disease in both groups, evaluated by hepatic ultrasound, in low-socioeconomic level children, independent of nutritional condition and without significant association with insulin resistance, emphasizes that especially in developing countries, other risk factors such as micronutrient deficiencies (e.g. vitamin A) are involved.

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