Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.

Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases.