scholarly journals Changes in LXRα phosphorylation promote a novel diet-induced transcriptome that alters the transition from fatty liver to steatohepatitis

2017 ◽  
Author(s):  
Natalia Becares ◽  
Matthew C Gage ◽  
Lucia Martin-Gutierrez ◽  
Elina Shrestha ◽  
Rikah Louie ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Liver Steatosis ◽  
High Cholesterol Diet ◽  
Hepatic Inflammation ◽  
High Cholesterol ◽  
High Fat ◽  
Cholesterol Accumulation ◽  
Liver Transcriptome ◽  
Fibrotic Steatohepatitis ◽  
Liver X Receptor Alpha

SUMMARYUnderstanding the transition from fatty liver (steatosis) to inflammatory and fibrotic steatohepatitis, is key to define strategies that alter its progression. Here we show that, when challenged with a high fat-high cholesterol diet, mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα) exhibit reduced hepatic inflammation and fibrosis despite displaying enhanced steatosis. This is associated with a marked protection against cholesterol accumulation. Reduced steatohepatitis in S196A mice involves unique reprogramming of the liver transcriptome in response to the diet. Remarkably, impaired LXRα phosphorylation uncovers novel diet-specific/phosphorylation-sensitive genes, whose regulation does not simply mirror ligand-induced LXR activation. Regulation of these unique, dually responsive genes, is associated with the promotion of LXR and cofactor occupancy under a cholesterol-rich diet. Therefore, Ser196-LXRα phosphorylation acts as a novel nutritional sensor that triggers a unique diet-induced transcriptome, thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.

scholarly journals CBD Alleviates Liver Injuries in Alcoholics With High-Fat High-Cholesterol Diet Through Regulating NLRP3 Inflammasome–Pyroptosis Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuye Jiang ◽  
Yingying Gu ◽  
Yuanling Huang ◽  
Yujia Zhou ◽  
Nengzhi Pang ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Nlrp3 Inflammasome ◽  
Liver Diseases ◽  
Liver Steatosis ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Liver Injuries

Alcohol abuse and high-fat diet–induced liver diseases have been the most prevalent chronic liver diseases and the leading reasons for liver transplantation around the world. Cannabidiol (CBD) is a botanical component extracted from marijuana plants without psychoactive impact. In our previous reports, we found that CBD can prevent fatty liver induced by Lieber–DeCarli ethanol diet or non-alcoholic fatty liver disease (NAFLD) induced by high-fat high-cholesterol diet. The current work is a further study on whether CBD can alleviate liver injuries induced by ethanol plus high-fat high-cholesterol diet (EHFD), which is a model simulating heavy alcohol drinkers in a Western diet. A mice liver injury model induced by EHFD for 8 weeks was applied to explore the protective properties of CBD and the underlying mechanisms. We found that CBD prevented liver steatosis and oxidative stress induced by EHFD. CBD treatment inhibited macrophage recruitment and suppressed activation of NFκB–NLRP3–pyroptosis pathway in mice livers. The hepatoprotective property of CBD in the current model might be a result of inhibition of inflammation via alleviating activation of the hepatic NFκB–NLRP3 inflammasome–pyroptosis pathway by CBD.

Paraoxonase-1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach

2013 ◽  
Vol 12 (4) ◽  
pp. 1946-1955 ◽  
Author(s):  
Anabel García-Heredia ◽  
Elizabeth Kensicki ◽  
Robert P. Mohney ◽  
Anna Rull ◽  
Iris Triguero ◽  
...  
Keyword(s):  
Liver Steatosis ◽  
Paraoxonase 1 ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Severe Liver ◽  
Metabolomic Approach

Bifidobacterium adolescentis and Lactobacillus rhamnosus alleviate non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet through modulation of different gut microbiota-dependent pathways

2020 ◽  
Vol 11 (7) ◽  
pp. 6115-6127
Author(s):  
Gang Wang ◽  
Ting Jiao ◽  
Yue Xu ◽  
Daozheng Li ◽  
Qian Si ◽  
...  
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

B. adolescentis and L. rhamnosus alleviate non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet through modulation on different gut microbiota-dependent pathways. The SCFAs are important participants.

scholarly journals Temporal Development of Dyslipidemia and Nonalcoholic Fatty Liver Disease (NAFLD) in Syrian Hamsters Fed a High-Fat, High-Fructose, High-Cholesterol Diet

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 604
Author(s):  
Victoria Svop Jensen ◽  
Christian Fledelius ◽  
Erik Max Wulff ◽  
Jens Lykkesfeldt ◽  
Henning Hvid
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
High Fructose

The use of translationally relevant animal models is essential, also within the field of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Compared to frequently used mouse and rat models, the hamster may provide a higher degree of physiological similarity to humans in terms of lipid profile and lipoprotein metabolism. However, the effects in hamsters after long-term exposure to a NASH diet are not known. Male Syrian hamsters were fed either a high-fat, high-fructose, high-cholesterol diet (NASH diet) or control diets for up to 12 months. Plasma parameters were assessed at two weeks, one, four, eight and 12 months and liver histopathology and biochemistry was characterized after four, eight and 12 months on the experimental diets. After two weeks, hamsters on NASH diet had developed marked dyslipidemia, which persisted for the remainder of the study. Hepatic steatosis was present in NASH-fed hamsters after four months, and hepatic stellate cell activation and fibrosis was observed within four to eight months, respectively, in agreement with progression towards NASH. In summary, we demonstrate that hamsters rapidly develop dyslipidemia when fed a high-fat, high-fructose, high-cholesterol diet. Moreover, within four to eight months, the NASH-diet induced hepatic changes with resemblance to human NAFLD.

scholarly journals Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis

2017 ◽  
Vol 313 (5) ◽  
pp. G376-G385 ◽  
Author(s):  
Pooja Malhotra ◽  
Costica Aloman ◽  
Aparna Ankireddy ◽  
Hani Khadra ◽  
Kohtaro Ooka ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Liver ◽  
Nonalcoholic Steatohepatitis ◽  
Hepatic Inflammation ◽  
Wild Type ◽  
High Cholesterol ◽  
High Fat ◽  
Regulatory Processes ◽  
Element Binding Protein ◽  
Severe Fibrosis

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver. NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.

Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver

2007 ◽  
Vol 293 (4) ◽  
pp. G871-G877 ◽  
Author(s):  
Vladimir Savransky ◽  
Shannon Bevans ◽  
Ashika Nanayakkara ◽  
Jianguo Li ◽  
Philip L. Smith ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice ( n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 ± 58 U/l vs. 103 ± 16 U/l in the control group; P < 0.01) and AST (637 ± 37 U/l vs. 175 ± 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1β, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-α; and an increase in α1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

scholarly journals Efficacy of Dietary Lipid Control in Healing High-Fat and High-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats

PLoS ONE ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. e0145939 ◽  
Author(s):  
Hazuki Tamada ◽  
Hisao Naito ◽  
Kazuya Kitamori ◽  
Yumi Hayashi ◽  
Nozomi Yamagishi ◽  
...  
Keyword(s):  
Dietary Lipid ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat ◽  
Lipid Control ◽  
Fibrotic Steatohepatitis
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