Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload.

The liver lipid metabolism of older individuals canbecome impaired and the circadian rhythm of genes involved in lipid metabolism is also disturbed. Although the link between metabolism and circadian rhythms is already recognized, how these processes are decoupled in liver during aging is still largely unknown. Here, we show that the circadian rhythm for the transcription factor Egr-1 expression is shifted forward with age in male mice. Egr-1 deletion accelerates liver age-related metabolic dysfunction, which associates with increased triglyceride accumulation, disruption of the opposite rhythmic coupling of Egr-1 and Cidea (Cell Death Inducing DFFA Like Effector A) at the transcriptional level and large lipid droplet formation. Importantly, adjustment of the central clock with light via a 4-hour forward shift in 6-month-old mice, leads to recovery the rhythm shift of Egr-1 during aging and largely ameliorated liver metabolic dysfunction. All our collected data suggest that liver Egr-1 might integrate the central and peripheral rhythms and regulate metabolic homeostasis in the liver.

Non-alcoholic fatty liver disease (NAFLD) has been considered to be one of the most common chronic liver diseases. However, no validated pharmacological therapies have been officially proved in clinic due to its complex pathogenesis. The purpose of this study was to examine the protective effects of Corilagin (referred to Cori) against NAFLD in mice under a high fat diet (HFD) condition. Mice were fed either a normal control diet (NCD) or HFD with or without Cori (5 or 10 mg/kg body weight) for 15 weeks. In our results, Cori treatment significantly attenuated HFD-induced hepatic steatosis, high NAFLD activity score (NAD) and liver injury. Consistently, Cori treatment remarkably alleviated HFD-induced hepatic lipid accumulation (e.g., triglycerides (TG) and total cholesterol (TC) contents in liver), and improved plasma lipid concentrations (e.g., plasma TG, TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c)). Moreover, Cori treatment ameliorated NAFLD associated metabolic disorders such as glucose intolerance and insulin resistance in HFD-fed mice. Additionally, Cori treatment dramatically changed HFD-induced liver gene expression profiles, and identified overlapped differentially expressed genes (DEGs) between NCD vs. HFD group and HFD vs. HCR (high fat diet plus treatment with Cori) group. With these DEGs, we observed a marked enrichment of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which were closely associated with the metabolic balance in liver. Particularly, we found several potential hub proteins against NAFLD development with analyses of protein-protein interaction (PPI) network and qPCR assays. Collectively, our results revealed the important protective effects of Cori against the progress of NAFLD, which was probably mediated through improving dysregulated lipid metabolism and insulin resistance in HFD-fed mice. Additionally, Cori-dependent overlapped DEGs might serve as a featured NAFLD-associated gene expression signature for the diagnosis, treatment, as well as drug discovery and development of NAFLD in the near future.

Epinephrine was recently shown to induce a hypotension episode. Activation of β2-adrenoceptors with smooth muscle relaxation may be the underlying mechanism. This study investigated the effects of ICI 118551, a β2-adrenoceptors antagonist, on epinephrine-induced blood pressure reduction via different administration routes in rats. A total of 144 Sprague Dawley rats were equally randomized into 3 groups (intranasal, intravenous, and intra-arterial administration), each with 4 subgroups: saline + saline, ICI 118551 + saline, saline + epinephrine, and ICI 118551 + epinephrine. All rats were anesthetized while spontaneously breathing. Epinephrine was administered at doses of 5 μg/kg via nose, 0.25 μg/kg via femoral vein, and 0.1 μg/kg via aorta. Mean arterial pressure and heart rate were monitored. Mean arterial pressure decreased in all 3 saline + epinephrine subgroups after administration (P < 0.05), whereas it did not in other subgroups. Heart rate had no significant change in all subgroups. Epinephrine-induced blood pressure reduction can be prevented by ICI 118551 in rats, suggesting that the activation of β2-adrenoceptors contributes to blood pressure reduction.