scholarly journals FoxO1 is a critical regulator of hepatocyte lipid deposition in chronic stress mice

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7668
Author(s):  
Yun-zi Liu ◽  
Wei Peng ◽  
Ji-kuai Chen ◽  
Wen-jun Su ◽  
Wen-jie Yan ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Liver Lipid ◽  
Lipid Synthesis ◽  
Cellular Level ◽  
Lipid Deposition ◽  
Lipid Levels ◽  
Nonalcoholic Fatty Liver ◽  
Forkhead Box ◽  
Genes Expression ◽  
Biochemical Detection

Forkhead box O1 (FoxO1) is involved in lipid metabolisms. However, its role in chronic stress-related nonalcoholic fatty liver disease (NAFLD) is unclear. The scientific premise of our study was based on the finding that FoxO1 expression is increased in the liver of mice after chronic stress. It is important to understand the mechanisms involved in the activation of FoxO1 and how its function affects the liver lipid deposition. We employed a murine chronic stress model, in which mice were treated by plantar electrical stimulation and restraint for 6 weeks, and a cellular model, in which Hepa1–6 cells were treated with corticosterone. We also used a pharmacologic approach as1842856, a highly specific FoxO1 inhibitor. Lipid metabolism related genes levels were measured by qRT-PCR and the lipid levels by biochemical detection. We show that the level of FoxO1 is significantly elevated in the liver of chronic stress mice. Transcription factor FoxO1 regulates a lipid synthesis phenotype of hepatocyte that is involved in the development and progression of NAFLD. We have shown that inhibition of FoxO1 induced phenotypic conversion of hepatocytes and down-regulates lipid synthesis genes expression by hepatocytes, which contribute to lipid deposition in NAFLD. At the cellular level, the inhibitor of FoxO1 as1842856 can also attenuate the lipid deposition of Hepa1–6 cells induced by corticosterone. Targeting FoxO1 is a novel therapeutic target for chronic stress-related NAFLD.

scholarly journals The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

Biology ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 338
Author(s):  
Cecilia Östlund ◽  
Antonio Hernandez-Ono ◽  
Ji-Yeon Shin
Keyword(s):  
Public Health ◽  
Lipid Metabolism ◽  
Nuclear Envelope ◽  
Liver Lipid ◽  
Lipid Synthesis ◽  
Public Health Problem ◽  
Cellular Mechanisms ◽  
Nonalcoholic Fatty Liver ◽  
Pathogenic Mechanisms ◽  
Nuclear Lamins

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologically connected to the ER, where protein synthesis and lipid synthesis occurs. Emerging evidence points toward that the nuclear lamins and nuclear membrane-associated proteins are involved in lipid metabolism and homeostasis. We review published reports that link these nuclear envelope proteins to lipid metabolism. In particular, we focus on the recent work demonstrating the essential roles for the nuclear envelope-localized torsinA/lamina-associated polypeptide (LAP1) complex in hepatic steatosis, lipid secretion, and NASH development. We also discuss plausible pathogenic mechanisms by which the loss of either protein in hepatocytes leads to hepatic dyslipidemia and NASH development.

scholarly journals Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease and Urinary Chromium Loss in Obese Mice

2021 ◽  
Vol 14 (3) ◽  
pp. 267
Author(s):  
Geng-Ruei Chang ◽  
Po-Hsun Hou ◽  
Wei-Cheng Yang ◽  
Chao-Min Wang ◽  
Pei-Shan Fan ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Glucose Intolerance ◽  
Fatty Liver Disease ◽  
Renal Damage ◽  
Liver Lipid ◽  
Interleukin 1 ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

scholarly journals Circulating Levels of Pro-Neurotensin and Its Relationship with Nonalcoholic Steatohepatitis and Hepatic Lipid Metabolism

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 373
Author(s):  
Beatriz Villar ◽  
Laia Bertran ◽  
Carmen Aguilar ◽  
Jessica Binetti ◽  
Salomé Martínez ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Lipid ◽  
Normal Liver ◽  
Normal Weight ◽  
Published Data ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Liver Lipid Metabolism

Recent studies suggest a link between pro-neurotensin (pro-NT) and nonalcoholic fatty liver disease (NAFLD), but the published data are conflicting. Thus, we aimed to analyze pro-NT levels in women with morbid obesity (MO) and NAFLD to investigate if this molecule is involved in NAFLD and liver lipid metabolism. Plasma levels of pro-NT were determined in 56 subjects with MO and 18 with normal weight (NW). All patients with MO were subclassified according to their liver histology into the normal liver (NL, n = 20) and NAFLD (n = 36) groups. The NAFLD group had 17 subjects with simple steatosis (SS) and 19 with nonalcoholic steatohepatitis (NASH). We used a chemiluminescence sandwich immunoassay to quantify pro-NT in plasma and RT-qPCR to evaluate the hepatic mRNA levels of several lipid metabolism-related genes. We reported that pro-NT levels were significantly higher in MO with NAFLD than in MO without NAFLD. Additionally, pro-NT levels were higher in NASH patients than in NL. The hepatic expression of lipid metabolism-related genes was found to be altered in NAFLD, as previously reported. Additionally, although pro-NT levels correlated with LDL, there was no association with the main lipid metabolism-related genes. These findings suggest that pro-NT could be related to NAFLD progression.

Dietary Conjugated Linolenic Acid Modifies Body Fat Mass, and Serum and Liver Lipid Levels in Rats

2006 ◽  
pp. 92-105
Author(s):  
Toshio Iwata ◽  
Michihiro Sugano ◽  
Kazunari Tanaka ◽  
Takaya Yamamoto ◽  
Takeshi Kamegai ◽  
...  
Keyword(s):  
Linolenic Acid ◽  
Body Fat ◽  
Fat Mass ◽  
Liver Lipid ◽  
Body Fat Mass ◽  
Lipid Levels ◽  
Conjugated Linolenic Acid

Recurrent Reye's Syndrome Without Liver Lipid Deposition

1981 ◽  
Vol 16 (2) ◽  
pp. 45-51 ◽  
Author(s):  
Kenneth L. Cox ◽  
Robert A. Cannon
Keyword(s):  
Liver Lipid ◽  
Lipid Deposition ◽  
Reye's Syndrome

scholarly journals Apolipoprotein CIII Overexpression-Induced Hypertriglyceridemia Increases Nonalcoholic Fatty Liver Disease in Association with Inflammation and Cell Death

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Adriene A. Paiva ◽  
Helena F. Raposo ◽  
Amarylis C. B. A. Wanschel ◽  
Tarlliza R. Nardelli ◽  
Helena C. F. Oliveira
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Content ◽  
Fatty Liver Disease ◽  
Liver Lipid ◽  
Hepatic Insulin Resistance ◽  
Nonalcoholic Fatty Liver ◽  
Liver Lipid Content

Nonalcoholic fatty liver disease (NAFLD) is the principal manifestation of liver disease in obesity and metabolic syndrome. By comparing hypertriglyceridemic transgenic mice expressing apolipoprotein (apo) CIII with control nontransgenic (NTg) littermates, we demonstrated that overexpression of apoCIII, independent of a high-fat diet (HFD), produces NAFLD-like features, including increased liver lipid content; decreased antioxidant power; increased expression of TNFα, TNFα receptor, cleaved caspase-1, and interleukin-1β; decreased expression of adiponectin receptor-2; and increased cell death. This phenotype is aggravated and additional NAFLD features are differentially induced in apoCIII mice fed a HFD. HFD induced glucose intolerance together with increased gluconeogenesis, indicating hepatic insulin resistance. Additionally, the HFD led to marked increases in plasma TNFα (8-fold) and IL-6 (60%) in apoCIII mice. Cell death signaling (Bax/Bcl2), effector (caspase-3), and apoptosis were augmented in apoCIII mice regardless of whether a HFD or a low-fat diet was provided. Fenofibrate treatment reversed several of the effects associated with diet and apoCIII expression but did not normalize inflammatory traits even when liver lipid content was fully corrected. These results indicate that apoCIII and/or hypertriglyceridemia plays a major role in liver inflammation and cell death, which in turn increases susceptibility to and the severity of diet-induced NAFLD.

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