Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis
- PMID: 29382663
- DOI: 10.2337/db17-0799
Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis
Abstract
Mammalian genomes encode a huge number of long noncoding RNAs (lncRNAs) with unknown functions. This study determined the role and mechanism of a new lncRNA, lncRNA suppressor of hepatic gluconeogenesis and lipogenesis (lncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and patients with nonalcoholic fatty liver disease, the expression levels of mouse lncSHGL and its human homologous lncRNA B4GALT1-AS1 were reduced. Hepatic lncSHGL restoration improved hyperglycemia, insulin resistance, and steatosis in obese diabetic mice, whereas hepatic lncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. lncSHGL overexpression increased Akt phosphorylation and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas lncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, lncSHGL recruited heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) to enhance the translation efficiency of CALM mRNAs to increase calmodulin (CaM) protein level without affecting their transcription, leading to the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway and repression of the mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated the CaM/Akt pathway and repressed the mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, lncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating the lncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.
© 2018 by the American Diabetes Association.
Similar articles
-
Hepatic Activation of the FAM3C-HSF1-CaM Pathway Attenuates Hyperglycemia of Obese Diabetic Mice.Diabetes. 2017 May;66(5):1185-1197. doi: 10.2337/db16-0993. Epub 2017 Feb 28. Diabetes. 2017. PMID: 28246289
-
Long noncoding RNA lncARSR promotes hepatic lipogenesis via Akt/SREBP-1c pathway and contributes to the pathogenesis of nonalcoholic steatohepatitis.Biochem Biophys Res Commun. 2018 Apr 30;499(1):66-70. doi: 10.1016/j.bbrc.2018.03.127. Epub 2018 Mar 20. Biochem Biophys Res Commun. 2018. PMID: 29555473
-
NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.Diabetes. 2017 Jul;66(7):1819-1832. doi: 10.2337/db16-1172. Epub 2017 Apr 14. Diabetes. 2017. PMID: 28411267
-
FAM3 gene family: A promising therapeutical target for NAFLD and type 2 diabetes.Metabolism. 2018 Apr;81:71-82. doi: 10.1016/j.metabol.2017.12.001. Epub 2017 Dec 6. Metabolism. 2018. PMID: 29221790 Review.
-
Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.Diabetes Obes Metab. 2010 Oct;12 Suppl 2:83-92. doi: 10.1111/j.1463-1326.2010.01275.x. Diabetes Obes Metab. 2010. PMID: 21029304 Review.
Cited by
-
Long noncoding RNAs in lipid metabolism: literature review and conservation analysis across species.BMC Genomics. 2019 Nov 21;20(1):882. doi: 10.1186/s12864-019-6093-3. BMC Genomics. 2019. PMID: 31752679 Free PMC article. Review.
-
Signaling by LncRNAs: Structure, Cellular Homeostasis, and Disease Pathology.Cells. 2022 Aug 13;11(16):2517. doi: 10.3390/cells11162517. Cells. 2022. PMID: 36010595 Free PMC article. Review.
-
Long non-coding RNA LOC100133669 promotes cell proliferation in oesophageal squamous cell carcinoma.Cell Prolif. 2020 Apr;53(4):e12750. doi: 10.1111/cpr.12750. Epub 2020 Mar 4. Cell Prolif. 2020. PMID: 32130753 Free PMC article.
-
Long noncoding RNA HOXC-AS3 remodels lipid metabolism and promotes the proliferation of transformed macrophages in the glioma stem cell microenvironment by regulating the hnRNPA1/CaM axis.Heliyon. 2023 Aug 9;9(8):e19034. doi: 10.1016/j.heliyon.2023.e19034. eCollection 2023 Aug. Heliyon. 2023. PMID: 37609424 Free PMC article.
-
Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress.Front Endocrinol (Lausanne). 2020 Jul 16;11:457. doi: 10.3389/fendo.2020.00457. eCollection 2020. Front Endocrinol (Lausanne). 2020. PMID: 32765426 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous