Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling

Gut ◽  
2017 ◽  
Vol 67 (12) ◽  
pp. 2192-2203 ◽  
Author(s):  
Joaquim Javary ◽  
Nathalie Allain-Courtois ◽  
Nicolas Saucisse ◽  
Pierre Costet ◽  
Capucine Heraud ◽  
...  

ObjectiveThe AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver.Design and resultsWe generated an inducible liver-specific Reptin knockout (RepinLKO) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia. This was associated with decreased hepatic mTOR protein abundance. Further experiments in primary hepatocytes demonstrated that Reptin maintains mTOR protein level through its ATPase activity. Unexpectedly, loss or inhibition of Reptin induced an opposite effect on mTORC1 and mTORC2 signalling, with: (1) strong inhibition of hepatic mTORC1 activity, likely responsible for the reduction of hepatocytes cell size, for decreased de novo lipogenesis and cholesterol transcriptional programmes and (2) enhancement of mTORC2 activity associated with inhibition of the gluconeogenesis transcriptional programme and hepatic glucose production. Consequently, the role of hepatic Reptin in the pathogenesis of insulin resistance (IR) and non-alcoholic fatty liver disease consecutive to a high-fat diet was investigated. We found that Reptin deletion completely rescued pathological phenotypes associated with IR, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hepatic steatosis.ConclusionWe show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1822
Author(s):  
Christian von Loeffelholz ◽  
Sina M. Coldewey ◽  
Andreas L. Birkenfeld

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.


2000 ◽  
Vol 278 (4) ◽  
pp. R956-R963 ◽  
Author(s):  
Jean-Michel Weber ◽  
Deena S. Shanghavi

The rate of hepatic glucose production (Ra glucose) of rainbow trout ( Oncorhynchus mykiss) was measured in vivo by continuous infusion of [6-3H]glucose and in vitro on isolated hepatocytes to examine the role of epinephrine (Epi) in its regulation. By elevating Epi concentration and/or blocking β-adrenoreceptors with propranolol (Prop), our goals were to investigate the mechanism for Epi-induced hyperglycemia to determine the possible role played by basal Epi concentration in maintaining resting Ra glucose and to assess indirect effects of Epi in the intact animal. In vivo infusion of Epi caused hyperglycemia (3.75 ± 0.16 to 8.75 ± 0.54 mM) and a twofold increase in Ra glucose (6.57 ± 0.79 to 13.30 ± 1.78 μmol ⋅ kg− 1 ⋅ min− 1, n = 7), whereas Prop infusion decreased Ra from 7.65 ± 0.92 to 4.10 ± 0.56 μmol ⋅ kg− 1 ⋅ min− 1( n = 10). Isolated hepatocytes increased glucose production when treated with Epi, and this response was abolished in the presence of Prop. We conclude that Epi-induced trout hyperglycemia is entirely caused by an increase in Ra glucose, because the decrease in the rate of glucose disappearance normally seen in mammals does not occur in trout. Basal circulating levels of Epi are involved in maintaining resting Ra glucose. Epi stimulates in vitro glucose production in a dose-dependent manner, and its effects are mainly mediated by β-adrenoreceptors. Isolated trout hepatocytes produce glucose at one-half the basal rate measured in vivo, even when diet, temperature, and body size are standardized, and basal circulating Epi is responsible for part of this discrepancy. The relative increase in Ra glucose after Epi stimulation is similar in vivo and in vitro, suggesting that indirect in vivo effects of Epi, such as changes in hepatic blood flow or in other circulating hormones, do not play an important role in the regulation of glucose production in trout.


2021 ◽  
Author(s):  
Justine Lallement ◽  
Ilyès Raho ◽  
Gregory Merlen ◽  
Dominique Rainteau ◽  
Mikael Croyal ◽  
...  

Objectives: Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D). In this study, we aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice. Methods: In order to investigate hepatic role of de novo ceramides synthesis, we generated mice lacking serine palmitoyltransferase 2 (Sptlc2) in hepatocytes using the cre-lox system. SPTLC2 allows condensation of serine and palmitoylCoA and is the rate limiting-enzyme necessary for ceramide de novo synthesis. Sptlc2ΔHep and their littermate controls were fed with high fat diet (HFD) to induce metabolic disorders. Liver ceramides content and metabolic parameters as glucose tolerance, insulin sensitivity, and hepatic glucose production were assessed. As ceramides may have impact on bile acids (BA), we investigated BA pool composition, synthesis and transport. Finally, inflammation and apoptosis were measured in the liver using western blot analysis, pro-inflammatory cytokines expression level and immunohistochemistry. Results: Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic ceramides, especially C16:0-ceramide. Hepatic deletion of Sptlc2 in mice was also associated with an increased neutral sphingomyelinase 2 (nSmase2) expression, and a decreased sphingomyelin content in the liver. We showed that Sptlc2ΔHep mice are protected against body mass gain normally induced by HFD and displayed a decreased body fat mass. BA hydrophobicity was drastically decreased in Sptlc2ΔHep mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-murocholic acid T-MCA in BA pool composition of Sptlc2ΔHep mice was associated with a downregulation of the nuclear bile acid receptor FXR target genes in ileum and liver. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production in an insulin-independent manner. Finally, Sptlc2 disruption promoted progressive development of hepatic fibrosis, apoptosis and inflammation in an age-related manner. Conclusion: Our data demonstrate for the first time a potential compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis. In addition, our results highlight the role of hepatic sphingolipid modulation on hepatic glucose production through bile acid composition changes.


Metabolites ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 282 ◽  
Author(s):  
Fabienne Rajas ◽  
Amandine Gautier-Stein ◽  
Gilles Mithieux

Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.


2008 ◽  
Vol 42 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Sachie Nakamichi ◽  
Yoko Senga ◽  
Hiroshi Inoue ◽  
Aki Emi ◽  
Yasushi Matsuki ◽  
...  

Gene related to anergy in lymphocytes (GRAIL) is an E3 ubiquitin ligase that regulates energy in T-lymphocytes. Whereas, the relevance of GRAIL to T lymphocyte function is well established, the role of this protein in other cell types remains unknown. Given that GRAIL is abundant in the liver, we investigated the potential function of GRAIL in nutrient metabolism by generating mice in which the expression of GRAIL is reduced specifically in the liver. Adenovirus-mediated transfer of a short hairpin RNA specific for GRAIL mRNA markedly reduced the amounts of GRAIL mRNA and protein in the liver. Blood glucose levels of the mice with hepatic GRAIL deficiency did not differ from those of control animals in the fasted or fed states. However, these mice manifested glucose intolerance in association with a normal increase in plasma insulin levels during glucose challenge. The mice also manifested an increase in the serum concentration of free fatty acids, whereas the serum levels of cholesterol and triglyceride were unchanged. The hepatic abundance of mRNAs for glucose-6-phosphatase, catalytic (a key enzyme in hepatic glucose production) and for sterol regulatory element-binding transcription factor 1 (an important transcriptional regulator of lipogenesis) was increased in the mice with hepatic GRAIL deficiency, possibly contributing to the metabolic abnormalities of these animals. Our results thus demonstrate that GRAIL in the liver is essential for maintenance of normal glucose and lipid metabolism in living animals.


2021 ◽  
Author(s):  
Pablo Ranea-Robles ◽  
Hongjie Chen ◽  
Brandon Stauffer ◽  
Chunli Yu ◽  
Dipankar Bhattacharya ◽  
...  

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.


Open Biology ◽  
2021 ◽  
Vol 11 (9) ◽  
Author(s):  
Chang Guo ◽  
Chenxi Wang ◽  
Xia Deng ◽  
Jianqiang He ◽  
Ling Yang ◽  
...  

ANGPTL8 is an important cytokine, which is significantly increased in type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. Many studies have shown that ANGPTL8 can be used as a bio-marker of these metabolic disorders related diseases, and the baseline ANGPTL8 level has also been found to be positively correlated with retinopathy and all-cause mortality in patients with T2DM. This may be related to the inhibition of lipoprotein lipase activity and the reduction of circulating triglyceride (TG) clearance by ANGPTL8. Consistently, inhibition of ANGPTL8 seems to prevent or improve atherosclerosis. However, it is puzzling that ANGPTL8 seems to have a directing function for TG uptake in peripheral tissues; that is, ANGPTL8 specifically enhances the reserve and buffering function of white adipose tissue, which may alleviate the ectopic lipid accumulation to a certain extent. Furthermore, ANGPTL8 can improve insulin sensitivity and inhibit hepatic glucose production. These contradictory results lead to different opinions on the role of ANGPTL8 in metabolic disorders. In this paper, the correlation between ANGPTL8 and metabolic diseases, the regulation of ANGPTL8 and the physiological role of ANGPTL8 in the process of glucose and lipid metabolism were summarized, and the physiological/pathological significance of ANGPTL8 in the process of metabolic disorder was discussed.


2015 ◽  
Vol 226 (3) ◽  
pp. 207-217 ◽  
Author(s):  
João Paulo G Camporez ◽  
Mohamed Asrih ◽  
Dongyan Zhang ◽  
Mario Kahn ◽  
Varman T Samuel ◽  
...  

Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance.


2021 ◽  
Vol 7 (26) ◽  
pp. eabf3885
Author(s):  
Amandine Verlande ◽  
Sung Kook Chun ◽  
Maggie O. Goodson ◽  
Bridget M. Fortin ◽  
Hosung Bae ◽  
...  

Lung adenocarcinoma is associated with cachexia, which manifests as an inflammatory response that causes wasting of adipose tissue and skeletal muscle. We previously reported that lung tumor–bearing (TB) mice exhibit alterations in inflammatory and hormonal signaling that deregulate circadian pathways governing glucose and lipid metabolism in the liver. Here, we define the molecular mechanism of how de novo glucose production in the liver is enhanced in a model of lung adenocarcinoma. We found that elevation of serum glucagon levels stimulates cyclic adenosine monophosphate production and activates hepatic protein kinase A (PKA) signaling in TB mice. In turn, we found that PKA targets and destabilizes the circadian protein REV-ERBα, a negative transcriptional regulator of gluconeogenic genes, resulting in heightened de novo glucose production. Together, we identified that glucagon-activated PKA signaling regulates REV-ERBα stability to control hepatic glucose production in a model of lung cancer–associated cachexia.


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