Biology subjects

Brocker, C. N.

Publications and source records attributed to Brocker, C. N..

3 recordsLinked to original sources

bioRxiv2022

Long non-coding RNA G23Rik attenuates fasting-induced lipid accumulation in the liver

Peroxisome proliferator-activated receptor (PPAR) is a key mediator of lipid metabolism and metabolic stress in the liver. A recent study revealed that PPAR-dependent long non-coding RNAs (lncRNAs) play an important role in modulating metabolic stress and inflammation in the livers of fasted mice. Here hepatic lncRNA 3930402G23Rik (G23Rik) was found to have active peroxisome proliferator response elements (PPREs) within its promoter and is directly regulated by PPAR. Although G23Rik RNA was expressed to varying degrees in several tissues, the PPAR-dependent regulation of this lncRNA was only observed in the liver. Pharmacological activation of PPAR induced PPAR recruitment at the G23Rik promoter and a pronounced increase in hepatic G23Rik lncRNA expression. A G23Rik-null mouse line was developed to further characterize the function of this lncRNA in the liver. G23Rik-null mice were more susceptible to hepatic lipid accumulation in response to acute fasting. Histological analysis further revealed a pronounced buildup of lipid droplets and a significant increase in neutral triglycerides and lipids as indicated by enhance oil red O staining of liver sections. Hepatic cholesterol, non-esterified fatty acid, and triglyceride levels were significantly elevated in G23Rik-null mice and associated with induction of the lipid-metabolism related gene Cd36. These findings provide evidence for a lncRNA dependent mechanism by which PPAR attenuates hepatic lipid accumulation in response to metabolic stress through lncRNA G23Rik induction. Key pointsO_LI3930402G23Rik (G23Rik) is a liver-enriched long non-RNA. C_LIO_LIG23Rik is a PPARA target gene. C_LIO_LILoss of G23Rik increases hepatic lipid accumulation during fasting C_LI

physiology↗

bioRxiv2019

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation. Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC=\"FIGDIR/small/675785v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@1db1d5dorg.highwire.dtl.DTLVardef@64c8b2org.highwire.dtl.DTLVardef@b4402borg.highwire.dtl.DTLVardef@1e0fbba_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG

molecular biology↗

bioRxiv2019

Dietary intake regulates the circulating inflammatory monocyte pool

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPAR) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.\n\nHighlightsO_LIFasting reduces the numbers of peripheral pro-inflammatory monocytes in healthy humans and mice.\nC_LIO_LIA hepatic AMPK-PPAR energy-sensing axis controls homeostatic monocyte numbers via regulation of steady-state CCL2 production.\nC_LIO_LIFasting reduces monocyte metabolic and inflammatory activity.\nC_LIO_LIFasting improves chronic inflammatory diseases but does not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair.\nC_LI

immunology↗