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1.
Mol Metab ; 78: 101812, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37777009

ABSTRACT

OBJECTIVE: Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. METHODS: To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. RESULTS: Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. CONCLUSION: These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor.


Subject(s)
Insulin Resistance , N-Acetylneuraminic Acid , Mice , Animals , N-Acetylneuraminic Acid/metabolism , Glucagon , Muscle, Skeletal/metabolism , Liver/metabolism , Glucose , Insulin , Homeostasis , Polysaccharides
2.
NPJ Genom Med ; 7(1): 43, 2022 Jul 22.
Article in English | MEDLINE | ID: mdl-35869090

ABSTRACT

Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin's globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

3.
Article in English | MEDLINE | ID: mdl-35218934

ABSTRACT

Obesity leads to persistent increases in immune responses that contribute to cardiometabolic pathologies such as diabetes and cardiovascular disease. Pro-inflammatory macrophages infiltrate the expanding fat mass, which leads to increased production of cytokines such as tumor necrosis factor-alpha. Moreover, saturated fatty acids enhance signaling through the toll-like receptors involved in innate immunity. Herein we discuss the evidence that ceramides-which are intermediates in the biosynthetic pathway that produces sphingolipids-are essential intermediates that link these inflammatory signals to impaired tissue function. We discuss the mechanisms linking these immune insults to ceramide production and review the numerous ceramide actions that alter cellular metabolism, induce oxidative stress, and stimulate apoptosis. Lastly, we evaluate the correlation of ceramides in humans with inflammation-linked cardiometabolic disease and discuss preclinical studies which suggest that ceramide-lowering interventions may be an effective strategy to treat or prevent such maladies.


Subject(s)
Cardiovascular Diseases , Ceramides , Ceramides/metabolism , Humans , Signal Transduction , Sphingolipids/metabolism , Toll-Like Receptors
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