ArticlePloS one2015
Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Adipose Tissue Browning in MASLD and Its Molecular Mechanisms and Metabolic Crosstalk.Current obesity reports · 2026Review
- FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production.JHEP reports : innovation in hepatology · 2026Article
- Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis.eGastroenterology · 2024Article
- Insulin Regulation of Hepatic Lipid Homeostasis.Comprehensive Physiology · 2023Review
- Activation of Liver mTORC1 Protects Against NASH via Dual Regulation of VLDL-TAG Secretion and De Novo Lipogenesis.Cellular and molecular gastroenterology and hepatology · 2022Article
- Crosstalk between beta-adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high-fat diet-fed male mice.Physiological reports · 2021Article
- Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure.Cell death & disease · 2021Article
- Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet.Molecular medicine reports · 2020Article
- Loss of TSC complex enhances gluconeogenesis via upregulation ofProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Fermented Korean Red Ginseng Extract Enriched in Rd and Rg3 Protects against Non-Alcoholic Fatty Liver Disease through Regulation of mTORC1.Nutrients · 2019Article
- mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases.International journal of molecular sciences · 2018Review
- Systems Analysis of the Liver Transcriptome in Adult Male Zebrafish Exposed to the Plasticizer (2-Ethylhexyl) Phthalate (DEHP).Scientific reports · 2018Article
- Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease.Frontiers in endocrinology · 2018Review
- SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.Nature reviews. Endocrinology · 2017Review
- Mammalian target of rapamycin complex 1 and FoxO1 in the transcriptional control of lipolysis and de novo lipogenesis.Current opinion in endocrinology, diabetes, and obesity · 2017Article
- mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Loss of hepatic DEPTOR alters the metabolic transition to fasting.Molecular metabolism · 2017Article
- Autophagy in the liver: functions in health and disease.Nature reviews. Gastroenterology & hepatology · 2017Review
- Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.Cell reports · 2016Article
- Chlorogenic Acid: The Conceivable Chemosensitizer Leading to Cancer Growth Suppression.Journal of evidence-based integrative medicineArticle
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting de novo lipogenesis. However, mTORC1 hyperactivity per se does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the in vivo mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of Tsc1 and/or S6k1 in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6-14 weeks. Following 8 weeks of high-fat diet, the Tsc1-/-;S6k1-/- mice had lower body weights but higher liver TG levels compared to that of the Tsc1-/- mice. However, the loss of S6k1 did not relieve feedback inhibition of Akt activity in the Tsc1-/- livers. To overcome Akt suppression, Pten was deleted in Tsc1-/- livers, and the resultant mice showed improved glucose tolerance compared with the Tsc1-/- mice. However, liver TG levels were significantly reduced in the Tsc1-/-;Pten-/- mice compared to the Pten-/- mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (Srebp1c, Fasn) were elevated in the Tsc1-/-;Pten-/- livers, but this was counter-balanced by an up-regulation of Cpt1a involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our in vivo models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism in vivo.
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