How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). PURPOSEAND AIM: This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD

On the importance of the humidity flux for the surface mass balance in the accumulation zone of the Greenland Ice Sheet

It is highly uncertain how the humidity flux between the snow surface and the atmosphere contributes to the surface mass balance (SMB) of the interior Greenland Ice Sheet (GrIS). Due to sparse observations, evaluations of the simulated humidity flux are limited. Model-based estimates of the humidity flux contribution to the SMB are, therefore, unconstrained and even disagree in magnitude and sign. In this study, we evaluate the regional climate model MAR at the EGRIP (East Greenland Ice-Core Project) site in the accumulation zone of the GrIS. We use a combined dataset of continuous one-level bulk estimates of the humidity flux covering the period 05/2016&ndash;08/2019 and direct eddy-covariance humidity flux measurements from all four summer seasons. In summer, we document a bias of too little sublimation (-1.3 W m&minus;2) caused by a cold bias in both air and surface temperature leading to a reduced humidity gradient. In winter, MAR overestimates deposition by about one order of magnitude. This is a consequence of an overestimated temperature gradient in too stable atmospheric conditions compared to observations. Both systematic errors cause a large discrepancy in the annual net humidity flux between the model and observations of -9 mm w. eq. yr&minus;1. Remarkably, the simulated net annual humidity flux contributes positively to the SMB, contrary to observations documenting a net sublimation flux. We correct the systematic errors by applying a simple but effective correction function to the simulated latent heat flux. Using this correction, we find that 5.1 % of the annual mass gain at the EGRIP site sublimates again, and 4.3 % of the total mass gain is deposited vapor from the near-surface air. The estimated net humidity flux contribution to the annual SMB is about -1 % (net sublimation) compared to +5.6 % for the uncorrected simulation. In summer, the corrected MAR simulation shows that deposition accounts for 9.6 % of the total mass gain and that 31 % of the total mass gain at the EGRIP site sublimates again. The net fluxes contribute to -32 % of the summer SMB. These results demonstrate that the humidity flux is a major driver of the summer SMB in the accumulation zone of the GrIS and highlight that even small changes could increase its importance for the annual SMB in a warming climate.</p

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites

Growth differentiation factor 7 autocrine signaling promotes hepatic progenitor cell expansion in liver fibrosis

BACKGROUND AND AIM: Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver.METHODS: GDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids.RESULTS: GDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids.CONCLUSIONS: Collectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease.</p

Now or Never: Environmental Protection under Hyperbolic Discounting

The author analyzes the optimal investment in environmental protection in a model of non-overlapping hyperbolically discounting agents. He shows that, in the long run and in the absence of a commitment device, society is stuck in a situation where all agents prefer further investments, yet no agent invests. This holds no matter whether agents are aware of the time inconsistency of their preferences. As a consequence, awareness of the time-inconsistency problem poses at best a short run remedy. Moreover, such an outcome may be Pareto inefficient and may explain the weak performance of long-run environmental policies. Special issue “Discounting the Long-Run Future and Sustainable Development

Protective effect of metformin against palmitate-induced hepatic cell death

Lipotoxicity causes hepatic cell death and therefore plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metformin, a first-line anti-diabetic drug, has shown a potential protective effect against NAFLD. However, the underlying mechanism is still not clear. In this study, we aim to understand the molecular mechanism of the protective effect of metformin in NAFLD, focusing on lipotoxicity. Cell death was studied in HepG2 cells and primary rat hepatocytes exposed to palmitate and metformin. Metformin ameliorated palmitate-induced necrosis and apoptosis (decreased caspase-3/7 activity by 52% and 57% respectively) in HepG2 cells. Metformin also reduced palmitate-induced necrosis in primary rat hepatocytes (P < 0.05). The protective effect of metformin is not due to reducing intracellular lipid content or activation of AMPK signaling pathways. Metformin and a low concentration (0.1 μmol/L) of rotenone showed moderate inhibition on mitochondrial respiration indicated by reduced basal and maximal mitochondrial respiration and proton leak in HepG2 cells. Moreover, metformin and rotenone (0.1 μmol/L) preserved mitochondrial membrane potential in both HepG2 cells and primary rat hepatocytes. In addition, metformin and rotenone (0.1 μmol/L) also reduces reactive oxygen species (ROS) production and increase superoxide dismutase 2 (SOD2) expression. Our results establish that metformin AMPK-independently protects against PA-induced hepatic cell death by moderate inhibition of the mitochondrial respiratory chain, recovering mitochondrial function, decreasing cellular ROS production, and inducing SOD2 expression, indicating that metformin may have beneficial actions beyond its glucose-lowering effect and also suggests that mitochondrial complex І may be a therapeutic target in NAFLD

Action plan for deriving dynamic RES-E policies

The core objective of this project is to facilitate a continuous and significant increase in the share of RESE with minimal costs to European citizen. To identify the most important strategies (e.g. Tradable Green Certificates, Feed-In Tariffs, Investment Subsidies, Emissions Trading, CO2-taxes) in a dynamic way the computer-based toolbox Green-X has been developed. Although within the scope of this project it has not been feasible to investigate all possible issues within this field, the cases analysed cover not only the needs and opportunities at the level of the national Member States, but also those at the level ofthe EU. However, the most important ones have been treated thoroughly. This report, which is the final outcome from the Green-X project (Contract No: ENG2-CT-2002- 00607), with funding from the European Commission, DG Research, provides recommendations on the way forward for the promotion of renewable energy for electricity generation in the EU. It is addressed primarily to energy policy maker, as well as to other people interested in renewable energy and energy policy