The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca²⁺ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca²⁺ is intricately compartmentalized, and the Ca²⁺ flow is tightly controlled by a network of Ca²⁺ transport and buffering proteins. Impaired Ca²⁺ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca²⁺ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca²⁺ signaling as a potential therapeutic approach.

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that has anti-angiogenic, anti-proliferative, neurotrophic and immunomodulatory properties. PEDF has recently emerged as a critical metabolic regulatory protein since the discovery of its modulatory activities in the lipolytic pathway by binding to adipose triglyceride lipase (ATGL). Despite being beneficial in maintaining the homeostasis of hepatic lipid accumulation, PEDF has been uncovered an unfavorable role associated with insulin resistance. The molecular events that connect these two apparent distinct observations have been controversial and remained largely unknown. Therefore in this short review, we attempt to summarize the current findings of PEDF regarding its lipid metabolic functions and provide perspectives in identifying PEDF as a potential therapeutic target in lipid disorders.

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.

Adipogenesis is a tightly regulated cellular process that involves the action of multiple signaling pathways. Characterization of regulators that are associated with adipose development is crucial to understanding the mechanisms underlying obesity and other metabolic disorders. Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that was first described as a neurotrophic factor. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, was characterized as its binding partner. In this study, we investigated the downstream effects of PEDF on adipogenic differentiation using rat adipose-derived stem cells (AdSCs) and the mouse pre-adipocyte cell line 3T3-L1. Knocking down PEDF in differentiating cells resulted in elevated levels of ATGL and CD36, as well as other adipogenic markers, with a concomitant increase in adipocyte number. CD36, a scavenger receptor for a variety of ligands, regulated proliferation and lipogenic gene expression during adipogenesis. The CD36 increase due to PEDF down-regulation might be a result of elevated PPARγ. We further demonstrated that PEDF expression was regulated by dexamethasone, a synthetic glucocorticoid that is widely used for adipogenesis at the transcriptional level. Taken together, our findings highlight that PEDF negatively regulates adipogenesis through the regulation of various signaling intermediates, and it may play a crucial role in lipid metabolic disorders.

Background: Living donor liver transplantation (LDLT) has been developed as one of gold standard treatments for end-stage liver disease. Mental health is a required selection criterion for adult living liver donors and may influence the quality of life after operation. Patients and methods: A total of 1,210 potential living donor candidates for liver transplantation (LT) underwent psychosocial evaluation that included a semi-structured interview, multi-choice self-reported inventory (Beck Depression Inventory-2nd edition [BDI-II], Beck Anxiety Inventory [BAI]), and the family APGAR (Adaptability, Partnership, Growth, Affection, Resolve) index. The test results were compared by family relationships, and subgroups were classified based on the donation type: 1) parents to children, 2) grown children to parents, 3) siblings to siblings, 4) spouses to spouses, and 5) other relatives to other relatives. Results: The BDI-II (P < 0.001) and BAI differed considerably according to the donation type in potential donor candidates. Compared with other subgroups, parents donating to their children suffered the most severe psychological stress before LDLT and exhibited more depressive (P < 0.001) and anxiety symptoms. However, the stress associated with grown children donating to their parents, siblings, and spouses was not significantly higher than it was for other relatives. Furthermore, a significant negative correlation existed between family APGAR scores and the severity of depression and anxiety (P < 0.001) among potential donor candidates. Conclusion: These results indicate the importance of understanding potential donor candidates’ psychological characteristics before LT. Greater anxiety and depression may be exhibited by parent donors due to the distress from fears of death or illness of the recipients, or their guilty feeling for their child. Additionally, family dysfunction also revealed more depression and anxiety. Such donor candidates should be given more extensive pre-donation counseling for minimizing pre-LDLT psychological stress.