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Restricting chromatin access improves liver health. Ion channels and tumor aggressiveness. Sphingolipid mutations drive cognitive impairments. Read about articles on these topics recently published in the Journal of Lipid Research.

Restricting chromatin access improves liver health

Nonalcoholic fatty acid liver disease, or NAFLD, is a condition in which excess fat builds up in the liver. This condition can lead to liver inflammation and cirrhosis, and with more than 25% of the global population affected and no approved treatments, it has become a public health issue. Studies have shown that NAFLD development and progression are correlated with epigenetic changes, including changes in histone methylation patterns. Histone methylation is a reversible process, and scientists have begun to view demethylases, the enzymes mediating the removal of methyl groups from modified histones, as attractive targets for NAFLD treatment.

In a recent published in the Journal of Lipid Research, Zifeng Yang and Siyao Zhang at Wuhan University showed that lysine-specific histone demethylase 1, or KDM1A, could be a potential therapeutic target for NAFLD. KDM1A regulates gene expression by controlling chromatin accessibility for transcription through the removal of methyl groups from lysine residues present on histone protein 3. The authors found increased levels of KDM1A protein in liver samples from patients with NAFLD and in monkeys with a similar diet-induced condition.

Using mice genetically altered to have NAFLD, the team observed that mice lacking KDM1A in the liver showed improved lipid metabolism, with decreased accumulation of fatty acids due to inhibition of lipogenesis and fatty acid uptake, and less inflammation compared to controls. Conversely, mice overexpressing KDM1A presented increased fat accumulation and inflammation in the liver. Mechanistically, they found that KDM1A elevates the chromatin accessibility of genes associated with inflammation, lipid metabolism and glucose metabolism.

The authors suggested that KDM1A could be a promising therapeutic target for NAFLD, as several KDM1A inhibitors are being used in clinical trials for diverse cancers. However, future studies will need to evaluate the global function of KDM1A beyond its role in the liver.    

Ion channels and tumor aggressiveness

Ion channels emerged recently as key factors that control tumor characteristics, with growing evidence suggesting a correlation between tumor aggressiveness, or how fast a tumor can grow and spread, and various ion channel aberrations. Small conductance calcium-activated potassium channels, or SK, are expressed in different types of cancer cells. SK3 channels can promote cancer cell migration. However, scientists do not know how SK3 channels are regulated.

In a recent in the Journal of Lipid Research, Marion Papin, Delphine Fontaine and their team at the University of Tours, France, defined how endogenous ether lipids, or ELs, regulate SK3 channels. Within membranes, ELs can form alkyl phospholipids, if the ether bond is saturated, or alkenyl phospholipids, with a vinyl-ether bond. The authors found that suppressing two key enzymes in EL synthesis, alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, decreased SK3 expression. Mechanistically, this suppression drove the expression of two microRNAs, which decreased cancer cell SK3-dependent calcium entry cell migration as well as cell adhesion and invasion.

These data suggest that the composition of alkyl- or alkenyl-ELs could be used to manipulate SK3 channels to control cancer cell aggression. Future research is needed to examine the role of SK3 channels in neurodegenerative and cardiovascular diseases, which both feature reduced ether lipids levels.

Sphingolipid mutations drive cognitive impairments

Sphingolipids are a major class of lipids that are enriched in the nervous system. They serve as membrane constituents and signaling molecules and play crucial roles in neuronal development and function. Alterations in sphingolipid levels and metabolism have been linked to neurological disorders such as Alzheimer’s and Parkinson’s disease, making them a candidate target for therapeutic intervention.

In a recent in the Journal of Lipid Research, Michele Dei Cas and colleagues at the Universit脿 degli Studi di Milano dissected the mechanism behind pathogenic mutations of sphingolipid delta-4-desaturase, or DEGS1, an enzyme in the ceramide synthesis pathway. Patients with these mutations have neurodevelopmental disorders characterized by reduced myelin deposits in the central nervous system, which can cause severe neuromotor and cognitive impairments as well as early mortality.

The authors showed that the DEGS1 mutations caused low protein expression. In addition, they found that the DEGS1 mutant proteins had impaired catalytic function. The group concluded that both loss of function and reduced protein levels are relevant in disease pathogenesis and asserted that these results could be useful for future characterizations of novel DEGS1 variants.