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Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. Liver-specific G6pc knockout (L-G6pc-/- ) mice were treated with AAV2/8-shChREBP to normalize hepatic ChREBP activity to levels observed in wildtype (L-G6pc+/+ ) mice receiving AAV8-shScramble. Hepatic ChREBP knockdown markedly increased liver weight and hepatocyte size in L-G6pc-/- mice. This was associated with hepatic accumulation of G6P, glycogen and lipids, while the expression of glycolytic and lipogenic genes was reduced. Enzyme activities, flux measurements, hepatic metabolite analysis and VLDL-TG secretion assays revealed that hepatic ChREBP knockdown reduced downstream glycolysis and de novo lipogenesis, but also strongly suppressed hepatic VLDL lipidation hence promoting the storage of 'old fat'. Interestingly, enhanced VLDL-TG secretion in shScramble-treated L-G6pc-/- mice associated with a ChREBP-dependent induction of the VLDL lipidation proteins MTTP and TM6SF2, the latter being confirmed by ChIP-PCR. CONCLUSION: Attenuation of hepatic ChREBP induction in GSD Ia liver aggravates hepatomegaly due to further accumulation of glycogen and lipids as a result of reduced glycolysis and suppressed VLDL-TG secretion. TM6SF2, critical for VLDL formation, was identified as a novel ChREBP target in mouse liver. Altogether, our data show that enhanced ChREBP activity limits NAFLD development in GSD Ia by balancing hepatic TG production and -secretion.

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Floods are extreme events that can have large impacts on human societies and ecosystems. They arise from a multitude of causes and can have very different consequences depending on regional and local circumstances. Floods are part of the natural hydrological cycle, but adverse impacts arise when water masses inundate infrastructures and land that cannot cope with the excessive water. Major flood disasters in Europe have caused loss of lives and economic loss that amount to billions of euro, but aggregated over large areas small local floods also produce significant losses. Analyses of trends of past flood events suggest flood hazard may have increased in parts of Europe. Available evidence suggests high flows have been increasing in northern Europe, especially in western Britain and coastal Scandinavia. Regional patterns are, however, diverse, with many weak negative trends occurring in northern Europe as well, and a very mixed pattern in central Europe. Across most of the continent, however, urbanisation and the accumulation of assets in flood prone areas have led to increasing trends in the damages and economic consequences of floods. Global warming may reduce flood hazard in areas that are dominated by annual snowmelt floods, except in those regions where a sharp increase in winter snowfalls outweighs the effects of a warmer and shorter snow season. In other parts of Europe there is greater uncertainty in how flood hazard will change due to climate change. Increases in extreme river flows have, however, been predicted in several studies and may occur over relatively short time spans. Flood risk management is a demanding task that requires careful analysis of flood hazards and their causes, assessments of the magnitude of the risks, systematic planning to reduce risks and adaptation in the face of possible change. Dam safety is a major issue in dealing with flood risks. Flood risk management requires appropriate institutions, technical solutions and functioning go

Floods are extreme events that can have large impacts on human societies and ecosystems. They arise from a multitude of causes and can have very different consequences depending on regional and local circumstances. Floods are part of the natural hydrological cycle, but adverse impacts arise when water masses inundate infrastructures and land that cannot cope with the excessive water. Major flood disasters in Europe have caused loss of lives and economic loss that amount to billions of euro, but aggregated over large areas small local floods also produce significant losses. Analyses of trends of past flood events suggest flood hazard may have increased in parts of Europe. Available evidence suggests high flows have been increasing in northern Europe, especially in western Britain and coastal Scandinavia. Regional patterns are, however, diverse, with many weak negative trends occurring in northern Europe as well, and a very mixed pattern in central Europe. Across most of the continent, however, urbanisation and the accumulation of assets in flood prone areas have led to increasing trends in the damages and economic consequences of floods. Global warming may reduce flood hazard in areas that are dominated by annual snowmelt floods, except in those regions where a sharp increase in winter snowfalls outweighs the effects of a warmer and shorter snow season. In other parts of Europe there is greater uncertainty in how flood hazard will change due to climate change. Increases in extreme river flows have, however, been predicted in several studies and may occur over relatively short time spans. Flood risk management is a demanding task that requires careful analysis of flood hazards and their causes, assessments of the magnitude of the risks, systematic planning to reduce risks and adaptation in the face of possible change. Dam safety is a major issue in dealing with flood risks. Flood risk management requires appropriate institutions, technical solutions and functioning go