Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

Sapp, Valerie; Gaffney, Leah; EauClaire, Steven F.; Matthews, Randolph P.

doi:10.1002/hep.27284

Cited by 109 publications

(80 citation statements)

References 40 publications

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“…Therefore, our data clearly demonstrate that dietary protein intake and AAs stimulate fatty acid biosynthetic gene expression through an mTORC1-dependent manner. Consistent with this observation, recent investigation in zebrafish also has shown that mTORC1 activation is required for hepatic lipid accumulation, as rapamycin reverses hepatic lipid accumulation and associated gene expression changes (lipogenic, inflammatory, oxidative stress, and ER stress genes) (70).…”

Section: Dietary Protein and Aas Stimulate Fatty Acid Biosynthesis Insupporting

confidence: 60%

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Dai

Panserat

Kaushik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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(DNL) remains debatable in carnivorous fish. We aimed to evaluate and compare the response of hepatic lipogenic gene expression to dietary carbohydrate intake/glucose and dietary protein intake/amino acids (AAs) during acute stimulations using both in vivo and in vitro approaches. For the in vivo trial, three different diets and a controlledfeeding method were employed to supply fixed amount of dietary protein or carbohydrate in a single meal; for the in vitro trial, primary hepatocytes were stimulated with a low or high level of glucose (3 mM or 20 mM) and a low or high level of AAs (one-fold or four-fold concentrated AAs). In vitro data showed that a high level of AAs upregulated the expression of enzymes involved in DNL [fatty acid synthase (FAS) and ATP citrate lyase (ACLY)], lipid bioconversion [elongation of very long chain fatty acids like-5 (Elovl5), Elovl2, ⌬6 fatty acyl desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD1)], NADPH production [glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme (ME)], and transcriptional factor sterol regulatory element binding protein 1-like, while a high level of glucose only elevated the expression of ME. Data in trout liver also showed that high dietary protein intake induced higher lipogenic gene expression (FAS, ACLY, and Elovl2) regardless of dietary carbohydrate intake, while high carbohydrate intake markedly suppressed the expression of acetyl-CoA carboxylase (ACC) and Elovl5. Overall, we conclude that, unlike rodents or humans, hepatic fatty acid biosynthetic gene expression in rainbow trout is more responsive to dietary protein intake/AAs than dietary carbohydrate intake/glucose during acute stimulations. This discrepancy probably represents one important physiological and metabolic difference between carnivores and omnivores. target of rapamycin; fatty acid biosynthesis; lipogenesis; protein; carbohydrate; rainbow trout DE NOVO LIPOGENESIS (DNL) is the metabolic pathway that synthesizes fatty acids from excess carbon donors; these fatty acids can then be converted into triglycerides, the major energy storage form in vertebrates (43,83,85). In mammals, hepatic lipogenesis is very responsive to dietary modifications (40). Consumption of a diet rich in carbohydrates stimulates the lipogenic pathway, whereas consumption of a diet rich in lipids and poor in carbohydrates, or rich in polyunsaturated fatty acids decreases this metabolic pathway (40,86). A highcarbohydrate diet can induce hyperglycemia, thereby stimulating lipogenesis via several mechanisms (40). First, by being glycolytically converted to acetyl-CoA, glucose provides substrate for fatty acid synthesis. Secondly, glucose stimulates glycolytic and lipogenic gene expression (24). Finally, glucose stimulates the release of insulin from the pancreas, thereby activating insulin/Akt signaling pathway (40, 69), which stimulates hepatic lipogenesis via the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) (32). Regarding dietary protein, rodent data showed that the meta...

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Section: Dietary Protein and Aas Stimulate Fatty Acid Biosynthesis Insupporting

confidence: 60%

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Dai

Panserat

Kaushik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Inappropriate mTORC1 activation in NAFLD and CKD inhibits autophagy (23,67) and promotes insulin resistance, ectopic lipid accumulation, lipotoxicity, and proinflammatory monocyte recruitment in the liver and kidney (Fig. 2B) (24,25). Consistently, mTORC1 inhibition has reversed metabolic abnormalities and attenuated lipid accumulation, inflammation, and fibrosis in diverse models of NASH and CKD (68,69) and may represent a therapeutic option for NAFLD and CKD (70) ( Table 2).…”

Section: Role Of Cellular Energy Oxygen and Nutrient Sensorsmentioning

confidence: 90%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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“…The present study showed that serum mTOR levels and intra-hepatic mTOR expression were positively correlated with steatosis grade in HCV infected patients without HCC suggesting a possible role of mTOR in hepatic lipid accumulation. Previous studies demonstrated that mTOR gene and protein expression were up-regulated in patients with fatty liver diseases; while rapamycin prevented the development of hepatic steatosis [47,48]. Moreover, rapamycin reduced hepatic uptake of free fatty acids and triglycerides with alleviation of hepatic steatosis in hepatoblastoma HepG2 cells [49].…”

Section: Discussionmentioning

confidence: 97%

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Lashen¹

2017

JLRDT

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Background: In chronic hepatitis C (CHC) infection, liver disease progression results from viral persistence. Deregulation of target of rapamycin (TOR) signaling and autophagy is detected in viral infections and cancer. We studied the role of TOR and autophagy in the progression of CHC infection.Methods: 54 patients infected with HCV, [27 with CHC; 13 with cirrhosis and 14 with hepatocellular carcinoma (HCC)]; and 15 healthy subjects were included. Quantification of serum TOR was determined using enzyme linked immunosorbent assay. Tissue samples were immune-stained using TOR and autophagy protein 5 (Atg5) polyclonal antibodies. Expression of TOR and Atg5 was scored semi-quantitatively.Results: Expression and serum TOR were higher in HCC patients compared to patients without HCC (P< 0.05). Serum and expression of TOR were positively correlated to inflammation, fibrosis, steatosis and tumor characteristics (Alpha-fetoprotein, maximum diameter, tumor grade and CLIP stage) (P<0.05). Expression of Atg5 was inversely correlated with inflammation, fibrosis and tumor characteristics (P<0.05), Atg5 showed significant inverse correlation with serum and intra-hepatic expression of TOR (P<0.05). Serum TOR showed high sensitivity and specificity in discriminating infected patients with and without HCC at a cut-off value of 4.55 ng/ml [Area under ROC curve = 0.970]. Conclusion:Activation of TOR plays an important role in progression of HCV related liver disease possibly though autophagy suppression and they could be a potential therapeutic target. Serum TOR is a potential seromarker in discriminating HCV infected patients with and without HCC with high sensitivity and specificity.

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Fructose leads to hepatic steatosis in zebrafish that is reversed by mechanistic target of rapamycin (mTOR) inhibition

Cited by 109 publications

References 40 publications

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

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