TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD.

Background/Aims: Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. Methods: The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). Results: The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury of HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell-membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. Conclusions: The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.

DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD.

DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD.

A predictive model for the diagnosis of non-alcoholic fatty liver disease based on an integrated machine learning method.

Diagnostic markers for non-alcoholic fatty liver disease (NAFLD) are still needed for screening individuals at risk. In recent years, the machine learning method was used to search for the diagnostic markers of multiple diseases. In this study, we developed and validated a machine learning model to diagnose NAFLD using laboratory indicators. NAFLD patients and non-NAFLD controls were recruited in the training and validation cohorts. The laboratory indicators of the participants in the training cohort were collected, and six indicators including alanine aminotransferase/aspartate aminotransferase (ALT/AST), white blood cells (WBC), alpha-L-fucosidase (AFU), hemoglobin (Hb), triglycerides (TG) and gamma-glutamyl transpeptidase (GGT) were screened out with higher weights by an integrate machine learning method. The areas under the receiver operating characteristic curves (AUROCs) for the selected indicators using logistic regression (LR), random forest (RF) and support vector machine (SVM) were 0.814, 0.837 and 0.810, respectively. Then the binary logistic regression was used to construct the predictive model. What's more, the AUROC of the predicted model was 0.732 in the validation cohort of patients with NAFLD. And the combined AUROC of the six parameters was 0.716 in the mouse model fed with high-fat diet (HFD). In summary, we created a predictive model with six laboratory indicators for the diagnosis of NAFLD based on the machine learning method, which has the potential value for the diagnosis of the NAFLD.

Lipid-induced DRAM recruits STOM to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD.

The biogenesis and diagnostic value of exosomes in nonalcoholic fatty liver disease (NAFLD) are unclear. In this study, we revealed that the plasma exosome level was higher in patients with NAFLD than that in healthy controls. Damage-regulated autophagy modulator (DRAM) was identified as one of the genes related to exosome secretion in patients with NAFLD. Then, loss or knockdown of DRAM down-regulated exosome secretion from hepatic cells using a knockout mouse model and a knockdown cell model. DRAM knockout reversed high-fat diet­induced increase of secreted exosomes. Furthermore, DRAM knockdown inhibited fatty acid (FA)­induced lysosomal membrane permeabilization and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice. Last, FA-induced DRAM interacted with stomatin and promoted its lysosomal localization to enhance exosome secretion from hepatic cells. We revealed a DRAM-mediated mechanism for exosome secretion and provided the foundation for plasma exosomes as a potential biomarker for NAFLD.

Roles and regulatory mechanisms of miR-30b in cancer, cardiovascular disease, and metabolic disorders (Review).

MicroRNAs (miRNAs) are non-coding RNAs 21-23 nucleotides in length that regulate gene expression, and thereby modulate signaling pathways and protein synthesis in both physiological and pathogenic processes. miR-30b inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transformation in multiple types of cancer. In addition to its role in several types of neoplasias, miR-30b has been shown to exhibit essential roles in cardiovascular and metabolic diseases. In the present review, an overview of the biological functions of miR-30b and its role in the pathogenesis of neoplastic, cardiovascular and metabolic diseases is provided. miR-30b is a potential candidate for clinical development as a diagnostic and prognostic biomarker, therapeutic agent and drug target. However, further research is required to elucidate its role in health and disease and to harness its potential clinical utility.