Sterol Regulatory Element-binding Protein-1 (SREBP-1) Is Required to Regulate Glycogen Synthesis and Gluconeogenic Gene Expression in Mouse Liver

Armani

J cachexia sarcopenia muscle

et al. 2018

Background Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. Methods By mean of in vivo Plin2 down‐regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. Results We found that Plin2 down‐regulation was sufficient to induce a 30% increase of myofiber cross‐sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. Conclusions Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

Section: Discussionmentioning

confidence: 99%

Muscle‐specific Perilipin2 down‐regulation affects lipid metabolism and induces myofiber hypertrophy

Armani

J cachexia sarcopenia muscle

et al. 2018

“…Similarly, mice with liver-specific knockout of the gene encoding the protein phosphatase Shp1 develop NAFLD, but are protected from insulin resistance 100 . Hepatic carbohydrate responsive element-binding protein and sterol regulatory element-binding protein-1 have recently been independently implicated in dissociating NAFLD and insulin resistance in mice and humans 101,102 . In addition, mice with the gene encoding the lipase activator CGI-58 knocked down have profound hepatic steatosis due to suppression of hepatic triglyceride lipolysis.…”

Section: Dissociation Of Nafld and Hepatic Insulin Resistancementioning

confidence: 99%

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Perry

Samuel

Petersen

et al. 2014

Nature

948

738

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

“…However, recent models wherein Akt is unable to inhibit GSK3 have called into question the physiological relevance of GSK inhibition on glycogenesis [154–156]. Our group and others have implicated mTORC1-dependent activation of SREBP1 as a novel regulator in liver glycogen synthesis [151,157]. Similarly, a mTORC1/SREBP1 pathway plays an important role in lipogenesis in concert with the effects of mTORC1 on the phosphatidic acid phosphatase Lipin [143,148,158–160].…”

Section: Glycogen and Lipid Synthesismentioning

confidence: 99%

Phosphoinositides: Key modulators of energy metabolism

Bridges

Saltiel

2015

Phosphoinositides are key players in many trafficking and signaling pathways. Recent advances regarding the synthesis, location and functions of these lipids have dramatically improved our understanding of how and when these lipids are generated and what their roles are in animal physiology. In particular, phosphoinositides play a central role in insulin signaling, and manipulation of PtdIns(3,4,5)P3 levels in particular, may be an important potential therapeutic target for the alleviation of insulin resistance associated with obesity and the metabolic syndrome. In this article we review the metabolism, regulation and functional roles of phosphoinositides in insulin signaling and the regulation of energy metabolism. This article is part of a Special Issue entitled Phosphoinositides.