The RNA binding protein human antigen R is a gatekeeper of liver homeostasis.

BACKGROUND AND AIMS: NAFLD is initiated by steatosis and can progress through fibrosis and cirrhosis to HCC. The RNA binding protein human antigen R (HuR) controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet-induced hepatic steatosis. The present study aimed to understand the role of hepatocyte HuR in NAFLD development and progression to fibrosis and HCC. APPROACH AND RESULTS: Hepatocyte-specific, HuR-deficient mice and control HuR-sufficient mice were fed either a normal diet or an NAFLD-inducing diet. Hepatic lipid accumulation, inflammation, fibrosis, and HCC development were studied by histology, flow cytometry, quantitative PCR, and RNA sequencing. The liver lipidome was characterized by lipidomics analysis, and the HuR-RNA interactions in the liver were mapped by RNA immunoprecipitation sequencing. Hepatocyte-specific, HuR-deficient mice displayed spontaneous hepatic steatosis and fibrosis predisposition compared to control HuR-sufficient mice. On an NAFLD-inducing diet, hepatocyte-specific HuR deficiency resulted in exacerbated inflammation, fibrosis, and HCC-like tumor development. A multi-omic approach, including lipidomics, transcriptomics, and RNA immunoprecipitation sequencing revealed that HuR orchestrates a protective network of hepatic-metabolic and lipid homeostasis-maintaining pathways. Consistently, HuR-deficient livers accumulated, already at steady state, a triglyceride signature resembling that of NAFLD livers. Moreover, up-regulation of secreted phosphoprotein 1 expression mediated, at least partially, fibrosis development in hepatocyte-specific HuR deficiency on an NAFLD-inducing diet, as shown by experiments using antibody blockade of osteopontin. CONCLUSIONS: HuR is a gatekeeper of liver homeostasis, preventing NAFLD-related fibrosis and HCC, suggesting that the HuR-dependent network could be exploited therapeutically.

White matter synapses: form, function, and dysfunction.

Synaptic transmission in the CNS represents the classic mechanism through which neural cells communicate. While vesicular neurotransmitter release has been known to be the preserve of gray matter, it is now known that synaptic-style release of glutamate, the brain's major excitatory neurotransmitter, occurs deep in white matter. Here it permits communication between axons and glial cells, enabling axon activity to couple with high fidelity to glial physiology. As white matter is increasingly well-recognized as a substrate for disease, dysregulation of white matter synaptic transmission will play an important role in the development of pathologies as diverse as stroke, multiple sclerosis, Alzheimer disease, and schizophrenia. This review highlights progress in this new and important field.

Glia as transmitter sources and sensors in health and disease.

Glial cells express a bewildering array of neurotransmitter receptors. To illustrate the complexity of expression, we have assayed non-glutamatergic neurotransmitter receptor mRNA in isolated rat optic nerve, a preparation devoid of neurons and neuronal synapses and from which relatively pure "glial" RNA can be isolated. Of the 44 receptor subunits examined which span the GABA-A, nicotinic, adreno- and glycine receptor families, over three quarters were robustly expressed in this mixed population of white matter glial cells, with several expressed at higher levels than found in control whole brain RNA. In addition to the complexity of glial receptor expression, numerous neurotransmitter release mechanisms have been identified. We have focused on glutamate release from astrocytes, which can occur via at least seven distinct pathways and which is implicated in excitotoxic injury and are neurons and glia. Recent findings suggest that non-glutamatergic receptors can also mediate acute glial injury are also discussed.