The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPARα.

BACKGROUND AND AIMS: Peroxisome Proliferator-Activated Receptor α (PPARα) is a key regulator of hepatic lipid metabolism and therefore a promising therapeutic target against Metabolic-dysfunction Associated Steatotic Liver Diseases (MASLD). However, its expression and activity decrease during disease progression and several of its agonists did not achieve sufficient efficiency in clinical trials with, surprisingly, a lack of steatosis improvement. Here, we identified the Human leukocyte antigen-F Adjacent Transcript 10 (FAT10) as an inhibitor of PPARα lipid metabolic activity during MASLD progression. APPROACH AND RESULTS: In vivo, the expression of FAT10 is upregulated in human and murine MASLD livers upon disease progression and correlates negatively with PPARα expression. The increase of FAT10 occurs in hepatocytes in which both proteins interact. FAT10 silencing in vitro in hepatocytes increases PPARα target gene expression, promotes fatty acid oxidation and decreases intra-cellular lipid droplet content. In line, FAT10 overexpression in hepatocytes in vivo inhibits the lipid regulatory activity of PPARα in response to fasting and agonist treatment in conditions of physiological and pathological hepatic lipid overload. CONCLUSIONS: FAT10 is induced during MASLD development and interacts with PPARα resulting in a decreased lipid metabolic response of PPARα to fasting or agonist treatment. Inhibition of the FAT10-PPARα interaction may provide a means to design potential therapeutic strategies against MASLD.

Soil carbon stocks in forest-tundra ecotones along a 500 km latitudinal gradient in northern Norway.

As shrubs and trees are advancing into tundra ecosystems due to climate warming, litter input and microclimatic conditions affecting litter decomposition are likely to change. To assess how the upward shift of high-latitude treeline ecotones might affect soil organic carbon stocks (SOC), we sampled SOC stocks in the surface layers of 14 mountain birch forest-tundra ecotones along a 500 km latitudinal transect in northern Norway. Our objectives were to examine: (1) how SOC stocks differ between forest and tundra soils, and (2) the relative role of topography, vegetation and climate in explaining variability in SOC stock sizes. Overall, forest soils had higher SOC stocks (median: 2.01 kg m-2) than tundra soils (median: 1.33 kg m-2). However, SOC storage varied greatly within and between study sites. Two study sites had higher SOC stocks in the tundra than in the nearby forest, five sites had higher SOC stocks in the forest, and seven sites did not show differences in SOC stocks between forest and tundra soils. Thus, our results suggest that an upwards forest expansion does not necessarily lead to a change in SOC storage at all sites. Further, a partial least-squares regression (PLSR) model indicated that elevation, temperature, and slope may be promising indicators for SOC stock size at high-latitude treelines. Precipitation and vegetation were in comparison only of minor importance.