Aim: To assess the m6A methylome in mouse fatty liver induced by a high-fat diet (HFD). Materials & methods: MeRIP-seq was performed to identify differences in the m6A methylomes between the normal liver and fatty liver induced by an HFD. Results: As compared with the control group, the upmethylated coding genes upon feeding an HFD were primarily enriched in processes associated with lipid metabolism, while genes with downmethylation were enriched in processes associated with metabolism and translation. Furthermore, many RNA-binding proteins that potentially bind to differentially methylated m6A sites were mainly annotated in processes of RNA splicing. Conclusion: These findings suggest that differential m6A methylation may act on functional genes through RNA-binding proteins to regulate the metabolism of lipids in fatty liver disease.

Intensive oxidative stress occurs during high-fat-diet-induced hepatic fat deposition, suggesting a critical role for redox signaling in liver metabolism. Intriguingly, evidence shows that fasting could also result in redox-profile changes largely through reduced oxidant or increased antioxidant levels. However, a comprehensive landscape of redox-modified hepatic substrates is lacking, thereby hindering our understanding of liver metabolic homeostasis. We employed a proteomic approach combining iodoacetyl tandem mass tag and nanoliquid chromatography tandem mass spectrometry to quantitatively probe the effects of high-fat feeding and fasting on in vivo redox-based cysteine modifications. Compared with control groups, ∼60% of cysteine residues exhibited downregulated oxidation ratios by fasting, whereas ∼94% of these ratios were upregulated by high-fat feeding. Importantly, in fasted livers, proteins exhibiting diminished cysteine oxidation were annotated in pathways associated with fatty acid metabolism, carbohydrate metabolism, insulin, peroxisome proliferator-activated receptors, and oxidative respiratory chain signaling, suggesting that fasting-induced redox changes targeted major metabolic pathways and consequently resulted in hepatic lipid accumulation.

Translational regulation plays a critical role in gene expression. However, there are few genome-wide studies on translational regulation in non-alcoholic fatty liver disease (NAFLD), which is a severe noncommunicable epidemic worldwide. In this study, we performed RNC-mRNA (mRNAs bound to ribosome-nascent chain complex) sequencing and mRNA sequencing to probe the translation status of high-fat-diet (HFD) induced mouse fatty liver. Generally, in the HFD group compared to the control group, changes of translation ratios and changes in mRNA abundance had a negative correlation. The relative abundance of RNC-mRNAs and mRNAs were positively correlated, yet the former changed more slowly than the latter. However, the rate of change became more balanced when it came to the livers of mice that were fed the HFD plus lycopene, an antioxidant. This indicated relatively independent roles of translational modulation and transcriptional regulation. Furthermore, many genes were differentially regulated at the transcriptional or translational levels, suggesting a new screening strategy for functional genes. In conclusion, our analysis revealed the different and correlated role of translational control with transcriptional regulation in the HFD-induced mouse fatty liver relative to the control, which indicates critical roles of translational control for liver steatosis; thus, adding a new dimension towards a better understanding and improvement of treatment for NAFLD.

Background and Purpose Non‐alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis. Experimental Approach In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high‐fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum–mitochondrial linker was adopted to increase mitochondria‐associated membranes (MAMs) and MICU1‐EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel. Key Results Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD‐induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high‐calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD‐induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01‐μM·kg−1 bodyweight) can alleviate HFD‐induced hepatic steatosis. Conclusion and Implications These findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.

Plant long non-coding RNAs (lncRNAs) are widely accepted to play crucial roles during diverse biological processes. In recent years, thousands of lncRNAs related to the establishment of symbiosis, root nodule organogenesis and nodule development have been identified in legumes. However, lncRNAs involved in nodule senescence have not been reported. In this study, senescence-related lncRNAs were investigated in Medicago truncatula nodules by high-throughput strand-specific RNA-seq. A total of 4576 lncRNAs and 126 differentially expressed lncRNAs (DElncRNAs) were identified. We found that more than 60% lncRNAs were associated with transposable elements, especially TIR/Mutator and Helitron DNA transposons families. In addition, 49 DElncRNAs were predicted to be the targets of micro RNAs. Functional analysis showed that the largest sub-set of differently expressed target genes of DElncRNAs were associated with the membrane component. Of these, nearly half genes were related to material transport, suggesting that an important function of DElncRNAs during nodule senescence is the regulation of substance transport across membranes. Our findings will be helpful for understanding the functions of lncRNAs in nodule senescence and provide candidate lncRNAs for further research.

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Liver is an important organ for fat metabolism. Excessive intake of a high-fat/energy diet is a major cause of hepatic steatosis and its complications such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Supplementation with lycopene, a natural compound, is effective in lowering triglyceride levels in the liver, although the underlying mechanism at the translational level is unclear. In this study, mice were fed a high-fat diet (HFD) to induce hepatic steatosis and treated with or without lycopene. Translation omics and transcriptome sequencing were performed on the liver to explore the regulatory mechanism of lycopene in liver steatosis induced by HFD, and identify differentially expressed genes (DEGs). We identified 1,358 DEGs at the translational level. Through transcriptomics and translatomics joint analysis, we narrowed the range of functional genes to 112 DEGs and found that lycopene may affect lipid metabolism by regulating the expression of LPIN1 at the transcriptional and translational levels. This study provides a powerful tool for translatome and transcriptome integration and a new strategy for the screening of candidate genes.

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