SUMMARY
Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model where lncLSTR regulates a TDP-43/FXR/apoC2 dependent pathway to maintain systemic lipid homeostasis.
SUMMARY
To systemically identify long non-coding RNAs (lncRNAs) regulating energy metabolism, we performed transcriptome analyses to simultaneously profile mRNAs and lncRNAs in key metabolic organs in mice under pathophysiologically representative metabolic conditions. Of 4759 regulated lncRNAs, function-orientated filters yield 359 tissue-specifically regulated and metabolically sensitive lncRNAs which are predicted by lncRNA-mRNA correlation analyses to function in diverse aspects of energy metabolism. Specific regulations of liver metabolically sensitive lncRNAs (lncLMS) by nutrients, metabolic hormones and key transcription factors were further defined in primary hepatocytes. Combining genome-wide screens, bioinformatics function predictions and cell-based analyses, we developed an integrative roadmap to identify lncRNA metabolic regulators. An lncLMS was experimentally confirmed in mice to suppress lipogenesis by forming a negative feedback loop in the SREBP1c pathway. Taken together, this study supports that a class of lncRNAs function as important metabolic regulators, and establishes a framework for systemically investigating the role of lncRNAs in physiological homeostasis.
Apolipoprotein A-I (ApoA-I) is the most abundant protein constituent of high-density lipoprotein (HDL). Reduced plasma HDL and ApoA-I levels have been found to be associated with obesity and metabolic syndrome in human beings. However, whether or not ApoA-I has a direct effect on obesity is largely unknown. Here we analysed the anti-obesity effect of ApoA-I using two mouse models, a transgenic mouse with overexpression of ApoA-I and the mice administered with an ApoA-I mimetic peptide D-4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA-I overexpression and D-4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA-I overexpression and D-4F treatment enhanced energy expenditure in the mice. The mRNA level of uncoupling protein (UCP)1 in brown fat tissue was elevated by ApoA-I transgenic mice. ApoA-I and D-4F treatment was able to increase UCP1 mRNA and protein levels as well as to stimulate AMP-activated protein kinase (AMPK) phosphorylation in brown adipocytes in culture. Taken together, our results reveal that ApoA-I has an anti-obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue.
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