The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating <i>de novo</i> lipogenesis and cholesterol synthesis

OBJECTIVE: Obesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development. METHODS: A murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20(LKO)). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1–(13)C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways. RESULTS: Hepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20(LKO) mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20(LKO) mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20(LKO) mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20(LKO) mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice. CONCLUSIONS: The hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients

Flexible and Transparent All-Graphene Circuits for Quaternary Digital Modulations

In modern communication system, modulation is a key function that embeds the baseband signal (information) into a carrier wave so that it can be successfully broadcasted through a medium such as air or cables. A flexible signal modulation scheme is hence essential to wide range of applications based on flexible electronics. Here we report a fully bendable all-graphene modulator circuit with the capability to encode a carrier signal with quaternary digital information for the first time. By exploiting the ambipolarity and the nonlinearity in a graphene transistor, we demonstrated two types of quaternary modulation schemes: 4-ary amplitude-shift keying (4-ASK) and quadrature phase-shift keying (QPSK). Remarkably, 4-ASK and QPSK can be realized with just 1 and 2 all-graphene transistors, respectively, representing a drastic reduction in circuit complexity when compared with conventional digital modulators. In addition, the circuit is not only flexible but also highly transparent (~95% transmittance) owing to their all-graphene design with every component (channel, interconnects, load resistor, and source/drain/gate electrodes) fabricated from graphene films. Taken together, these results represent a significant step toward achieving a high speed communication system that can be monolithically integrated on a flexible and transparent platform.Comment: 29 pages, 8 figures, 1 tabl

P2SF: Physically-based Point Spread Function for digital image processing

P2SF is a tool aimed at estimating the spatially variant point spread function based on the ray-tracing computation of the pupil function. Only 6 parameters are required to describe a monochromatic PSF

Electromagnetic compatibility analysis of unstructured mains networks for high-speed data transmission: Part 2

Different approaches are described for the characterisation of the low voltage mains network that is used for high-speed data transmission broadband over power line (BPL). Part 1 investigated the disturbance scenario of these BPL devices and importance will be given to develop a new measurement procedure in Comite Internationale Special des Perturbations Radioelectrotechnique (CISPR) to estimate the high-frequency characteristics of AC mains networks. The improvements of the measurement method that can also be applied to other wire-based telecommunication systems will also be presented. Part 2 shows the definitions and comparisons of different symmetry factors. The transfer of the results on the compliance test for BPL devices will also be depicted.Electromagnetic compatibility in diffused communications system