High-fat Diet-induced Liver Injury Research Articles

235 RIP3 Deficiency Enhances High Fat Diet-Induced Liver Injury and Hepatocyte Apoptosis in Mice

235 RIP3 Deficiency Enhances High Fat Diet-Induced Liver Injury and Hepatocyte Apoptosis in Mice

High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice.

BackgroundIt is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome.MethodsWe examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice.ResultsHigh-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice.ConclusionsWe demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-015-0002-9) contains supplementary material, which is available to authorized users.

The Anti-Obesity Effect of Instant Pu-Erh Black Tea in Mice with Hydrogenated Oil Diet-Induced Obesity

Obesity is becoming a worldwide epidemic disease, and the incidence is increasing year by year. Drinking tea has been demonstrated to have multiple beneficial effects to obese patients. This article tested the effect of instant Pu-erh black tea on weight loss in diet-induced obese (DIO) mice. The results demonstrated that instant Pu-erh black tea was be able to reduce the mouse weight dose-dependently. Its effect is stronger than that of L-carnitine, a weight loss drug currently on the market. Instant Pu-erh black tea also accelerated lipid metabolism and eased the high-fat diet-induced liver injury.

The Anti-Obesity Effect of Instant Pu-Erh Ripe Tea in Mice with Hydrogenated Oil Diet-Induced Obesity

Obesity has become a fast growing epidemic in developing countries, as well as in some of the developing countries. Drinking Chinese tea has been demonstrated to have multiple beneficial effects to obese patients. It showed strong effect in reducing body fat and lowering blood sugar. This article tested the effect of instant Pu-erh ripe tea on weight loss in diet-induced obese (DIO) mice. The results demonstrated that instant Pu-erh ripe tea was be able to reduce the mouse weight dose-dependently. Its effect is stronger than that of L-carnitine, a weight loss drug currently on the market. Instant Pu-erh ripe tea also accelerated lipid metabolism and eased the high-fat diet-induced liver injury.

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe−/) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe−/− mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1α and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe−/− group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol- and obesity-induced liver injury.

Chicoric acid prevents obesity by attenuating hepatic steatosis, inflammation and oxidative stress in high-fat diet-fed mice

Chicoric acid, a natural phenolic acid, has been found to possess multiple biological properties. However, the antiobesity activity of chicoric acid remains unclear. In the present study, high-fat diet-induced obese C57BL/6J mice were used to investigate the antiobesity effect of chicoric acid in vivo. The results showed that chicoric acid significantly reduced body weight and lowered serum lipid parameters as well as homeostasis model assessment of insulin resistance (HOMA-IR) in HFD-fed mice. Meanwhile, chicoric acid appeared to attenuate high-fat diet-induced liver injury through decreasing hepatic steatosis and fatty acid synthase (FAS) levels, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and the Bax/Bcl-2 ratio in liver. Chicoric acid had a positive effect on obesity-associated hepatic inflammation via reducing TNF-α and IL-6 levels as well as protein expressions of COX-2 and p-JNK. High-fat diet mice treated with chicoric acid exhibited enhanced antioxidant defense system and reduced liver lipid peroxidation through increasing the activity of antioxidant enzymes and total antioxidant capacity (TAC) in liver. Furthermore, chicoric acid also regulated the levels of leptin and adiponectin as well as inhibited the protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Therefore, chicoric acid efficiently inhibited obesity in high-fat diet-fed mice through attenuating insulin resistance, liver injury and inflammation, enhancing antioxidant defense system, and regulating the secretions of adipocytokines and adipogenesis-associated proteins.

Isoliquiritigenin, an antioxidant flavonoid from licorice, inhibits high‐fat diet‐induced hepatic steatosis and oxidative injury through JNK1 inhibition

Isoliquiritigenin (ILQ), a flavonoid originated from Glycyrrhizae species, has an anti‐oxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor‐alpha (LXRalpha)‐mediated lipogenesis and steatosis in hepatocytes, and the underlying molecular basis. Treatment of ILQ antagonized the ability of LXRalpha agonist (T0901317) to activate sterol regulatory element binding protein‐1c, thereby repressing downstream lipogenic genes induction. ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNFalpha. JNK1, but not JNK2, increased LXRalpha phosphorylation at serine residues, promoting LXRalpha activation. The ability of ILQ to inhibit JNK1 led to the repression of T0901317‐inducible LXRalpha activation. In mice fed a high‐fat diet, ILQ treatment inhibited hepatic steatosis, as shown by a decrease in fat accumulation and repression of lipogenic genes. The results of blood chemistry and histopathology confirmed attenuation of high‐fat diet‐induced liver injury by ILQ. Moreover, ILQ inhibited oxidative stress, as shown by decreases in thiobarbituric acid reactive substance formation, iNOS and COX‐2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRalpha‐dependent hepatic steatosis through JNK1 inhibition, and protect hepatocytes from oxidative injury induced by fat accumulation.

Inhibition of liver X receptor-α-dependent hepatic steatosis by isoliquiritigenin, a licorice antioxidant flavonoid, as mediated by JNK1 inhibition

Isoliquiritigenin (ILQ), a flavonoid obtained from Glycyrrhizae species, has an antioxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor-α (LXRα)-mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis. Treatment with ILQ antagonized the ability of an LXRα agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), thereby repressing transcription of fatty acid synthase, acetyl-CoA carboxylase, ATP-binding cassette transporter-A1, and stearoyl-CoA desaturase-1. ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNFα. JNK1, but not JNK2, increased LXRα phosphorylation at serine residues, promoting LXRα activation. The ability of ILQ to inhibit JNK1 downstream of ASK1–MKK7 led to the repression of T0901317-inducible LXRα and SREBP-1c activation. In mice fed a high-fat diet, ILQ treatment inhibited hepatic steatosis, as shown by a decrease in fat accumulation and repression of lipogenic genes. The results of blood biochemistry and histopathology confirmed attenuation of high-fat diet-induced liver injury by ILQ. Moreover, ILQ inhibited oxidative stress, as indicated by decreases in thiobarbituric acid-reactive substance formation, iNOS and COX2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRα-dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation.