Persistent mTORC1 activation via Depdc5 deletion results in spontaneous hepatocellular carcinoma but does not exacerbate carcinogen- and high-fat diet-induced hepatic carcinogenesis in mice

Chronic obesity and insulin resistance are considered to inhibit contraction-induced muscle hypertrophy, through impairment of mTORC1 and muscle protein synthesis (MPS). A high-fat diet is known to rapidly induce obesity and insulin resistance within a month. However, the influence of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute resistance exercise (RE) is unclear. Thus, the purpose of this study was to investigate the effect of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute RE. Male Sprague-Dawley rats were randomly assigned to groups and fed a normal diet (ND), high-fat diet (HFD 4wk), or pair feed (PF 4wk) for 4 weeks. After dietary habituation, acute RE was performed on the gastrocnemius muscle via percutaneous electrical stimulation. The results showed that 4 weeks of a high fat-diet induced intramuscular lipid accumulation and insulin resistance, without affecting basal mTORC1 activity or MPS. The response of RE-induced mTORC1 activation and MPS was not altered by a high-fat diet. On the other hand, analysis of each fiber type demonstrated that response of MPS to an acute RE was disappeared specifically in type I and IIa fiber. These results indicate that a short-term high-fat diet causes anabolic resistance to acute RE, depending on the fiber type.

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Abstract 96: High iron or high fat diet show similar effects in inducing hepatocellular carcinoma in a mouse model

10.1158/1538-7445.sabcs18-96 ◽

2019 ◽

Author(s):

Hakim Bouamar ◽

Kalyan Kakarla ◽

Matyas Cserhati ◽

Fatima Ezzahra El Mroussi ◽

Francis E Sharkey ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Mouse Model ◽

High Fat Diet ◽

High Fat ◽

High Iron

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Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

10.1101/720540 ◽

2019 ◽

Author(s):

Erin J. Stephenson ◽

JeAnna R. Redd ◽

Detrick Snyder ◽

Quynh T. Tran ◽

Binbin Lu ◽

...

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

High Fat Diet ◽

High Fat ◽

Constitutive Activation ◽

Mechanistic Target Of Rapamycin ◽

Systemic Insulin Resistance ◽

Mtorc1 Signaling ◽

Futile Cycling ◽

Mtorc1 Activation

AbstractThe mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

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Dietary Choline Supplementation Attenuates High-Fat-Diet–Induced Hepatocellular Carcinoma in Mice

Journal of Nutrition ◽

10.1093/jn/nxz315 ◽

2019 ◽

Vol 150 (4) ◽

pp. 775-783 ◽

Cited By ~ 1

Author(s):

Amanda L Brown ◽

Kelsey Conrad ◽

Daniela S Allende ◽

Anthony D Gromovsky ◽

Renliang Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Suppressor Cells ◽

Therapeutic Benefit ◽

Tumor Burden ◽

High Fat ◽

Fed State ◽

Glucose Tolerance Tests ◽

Dietary Choline

ABSTRACT Background Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Choline deficiency has been well studied in the context of liver disease; however, less is known about the effects of choline supplementation in HCC. Objective The objective of this study was to test whether choline supplementation could influence the progression of HCC in a high-fat-diet (HFD)–driven mouse model. Methods Four-day-old male C57BL/6J mice were treated with the chemical carcinogen, 7,12-dimethylbenz[a]anthracene, and were randomly assigned at weaning to a cohort fed an HFD (60% kcal fat) or an HFD with supplemental choline (60% kcal fat, 1.2% choline; HFD+C) for 30 wk. Blood was isolated at 15 and 30 wk to measure immune cells by flow cytometry, and glucose-tolerance tests were performed 2 wk prior to killing. Overall tumor burden was quantified, hepatic lipids were measured enzymatically, and phosphatidylcholine species were measured by targeted MS methods. Gene expression and mitochondrial DNA were quantified by quantitative PCR. Results HFD+C mice exhibited a 50–90% increase in both circulating choline and betaine concentrations in the fed state (P ≤ 0.05). Choline supplementation resulted in a 55% decrease in total tumor numbers, a 67% decrease in tumor surface area, and a 50% decrease in hepatic steatosis after 30 wk of diet (P ≤ 0.05). Choline supplementation increased the abundance of mitochondria and the relative expression of β-oxidation genes by 21% and ∼75–100%, respectively, in the liver. HFD+C attenuated circulating myeloid-derived suppressor cells at 15 wk of feeding (P ≤ 0.05). Conclusions Choline supplementation attenuated HFD-induced HCC and hepatic steatosis in male C57BL/6J mice. These results suggest a therapeutic benefit of choline supplementation in blunting HCC progression.

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The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid

Medical Science Monitor ◽

10.12659/msm.919220 ◽

2020 ◽

Vol 26 ◽

Author(s):

Jinshan Wang ◽

Wentao Jiang

Keyword(s):

Hepatocellular Carcinoma ◽

Oleic Acid ◽

Liver Disease ◽

Mouse Model ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Carcinoma Cells ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Human Hepatocellular Carcinoma Cells

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Hepatocellular Carcinoma Emergence in Diabetic Mice with Non-Alcoholic Steatohepatitis Depends on Diet and Is Delayed in Liver Exhibiting an Active Immune Response

Cancers ◽

10.3390/cancers12061491 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1491

Author(s):

Mélanie Simoes Eugénio ◽

Muhammad Farooq ◽

Sarah Dion ◽

Christelle Devisme ◽

Céline Raguenes-Nicol ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Response ◽

High Fat Diet ◽

Liver Tumors ◽

High Cholesterol Diet ◽

Diabetic Mice ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

The Impact

The increase of the sedentary lifestyle and high-calorie diet have modified the etiological landscape of hepatocellular carcinoma (HCC), with a recrudescence of non-alcoholic fatty liver disease (NAFLD), especially in Western countries. The purpose of our study was to evaluate the impact of high-fat diet feeding on non-alcoholic steatohepatitis (NASH) establishment and HCC development. Streptozotocin-induced diabetic male mice were fed with high-fat-high-cholesterol diet (HFHCD) or high-fat-high-sugar diet (HFHSD) from 1 to 16 weeks. Even if liver tumors appear regardless of the high-fat diet, two distinct physiopathological patterns were evidenced, with much more severe NASH hallmarks (liver injury, inflammation and fibrosis) in diabetic mice fed with HFHCD. The mild hepatic injury, weak inflammation and fibrosis observed in HFHSD were interestingly associated with earlier emergence of more numerous liver tumors. When activated helper and cytotoxic T cells, detected by flow cytometry, infiltrated the liver of HFHCD-fed diabetic mice, a delay in the appearance of tumor nodules and a limitation of their numbers were observed, suggesting that the immune activities partly controlled tumor emergence. These data highlighted two different mouse models of HCC progression in diabetic mice depending on diet, which could be useful to evaluate new therapeutic approaches for HCC by targeting the immune response.

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