Non-alcoholic fatty liver disease (NAFLD), a metabolic-associated fatty liver disease, has become the most common chronic liver disease worldwide. Recently, the discovery of cuproptosis, a newly identified mode of cell death, further highlighted the importance of copper in maintaining metabolic homeostasis. An increasing number of studies have confirmed that liver copper metabolism is closely related to the pathogenesis of NAFLD. However, the relationship between NAFLD and copper metabolism, especially cuproptosis, remains unclear. In this review, we aim to summarize the current understanding of copper metabolism and its dysregulation, particularly the role of copper metabolism dysregulation in the pathogenesis of NAFLD. More importantly, this review emphasizes potential gene-targeted therapeutic strategies, challenges and the future of cuproptosis-related genes in the treatment of NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD.

Metabolic health is tightly regulated by neuro-hormonal control, and systemic metabolic dysfunction may arise from altered function of the hypothalamic-anterior pituitary axis (HAPA). Ancient experimental observations of hypothalamic obesity (HO) and liver cirrhosis occurring among animals subjected to hypothalamic injury can now be explained using the more recent concepts of lipotoxicity and metabolic dysfunction-associated steatotic liver disease (MASLD). Lipotoxicity, the range of abnormalities resulting from the harmful effects of fatty acids accumulated in organs outside of adipose tissue, is the common pathogenic factor underlying closely related conditions like hypothalamic syndrome, HO, and MASLD. The hormonal deficits and the array of metabolic and metabolomic disturbances that occur in cases of HO are discussed, along with the cellular and molecular mechanisms that lead, within the MASLD spectrum, from uncomplicated steatotic liver disease to steatohepatitis and cirrhosis. Emphasis is placed on knowledge gaps and how they can be addressed through novel studies. Future investigations should adopt precision medicine approaches by precisely defining the hormonal imbalances and metabolic dysfunctions involved in each individual patient with HO, thus paving the way for tailored management of MASLD that develops in the context of altered HAPA.

The obligate intracellular parasite Toxoplasma gondii can infect and replicate in any warm-blooded cell tested to date, but much of our knowledge about T. gondii cell biology comes from just one host cell type: human foreskin fibroblasts (HFFs). To expand our knowledge of host-parasite lipid interactions, we studied T. gondii in intestinal epithelial cells, the first site of host-parasite contact following oral infection and the exclusive site of parasite sexual development in feline hosts. We found that highly metabolic Caco-2 cells are permissive to T. gondii growth even when treated with high levels of linoleic acid (LA), a polyunsaturated fatty acid (PUFA) that kills parasites in HFFs. Caco-2 cells appear to sequester LA away from the parasite, preventing membrane disruptions and lipotoxicity that characterize LA-induced parasite death in HFFs. Our work is an important step toward understanding host-parasite interactions in feline intestinal epithelial cells, an understudied but important cell type in the T. gondii life cycle.

Epicardial adipose tissue (EAT) is a fat depot covering the heart. No physical barrier separates EAT from the myocardium, so EAT can easily affect the underlying cardiac muscle. EAT can participate in the development and progression of heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). In healthy humans, excess EAT is associated with impaired cardiac function and worse outcomes. In HFpEF, this trend continues: EAT amount is usually increased, and excess EAT correlates with worse function/outcomes. However, in HFrEF, the opposite is true: reduced EAT amount correlates with worse cardiac function/outcomes. Surprisingly, although EAT has beneficial effects on cardiac function, it aggravates ventricular arrhythmias. Here, we dissect these phenomena, trying to explain these paradoxical findings to find a target for novel heart failure therapies aimed at EAT rather than the myocardium itself. However, the success of this approach depends on a thorough understanding of interactions between EAT and the myocardium.

Lipotoxicity is defined as a prolonged metabolic imbalance of lipids that results in ectopic fat distribution in peripheral organs such as the liver, heart, and kidney. The harmful consequences of excessive lipid accumulation in cardiomyocytes cause cardiac lipotoxicity, which alters the structure and function of the heart. Obesity and diabetes are linked to lipotoxic cardiomyopathy. These anomalies might be caused by a harmful metabolic shift that accumulates toxic lipids and shifts glucose oxidation to less fatty acid oxidation. Research has linked fatty acids, fatty acyl coenzyme A, diacylglycerol, and ceramide to lipotoxic stress in cells. This stress can be brought on by apoptosis, impaired insulin signaling, endoplasmic reticulum stress, protein kinase C activation, p38 Ras-mitogen-activated protein kinase (MAPK) activation, or modification of peroxisome proliferator-activated receptors (PPARs) family members. Curcuma longa is used to extract curcumin, a hydrophobic polyphenol derivative with a variety of pharmacological characteristics. Throughout the years, curcumin has been utilized as an anti-inflammatory, antioxidant, anticancer, hepatoprotective, cardioprotective, anti-diabetic, and anti-obesity drug. Curcumin reduces cardiac lipotoxicity by inhibiting apoptosis and decreasing the expression of apoptosis-related proteins, reducing the expression of inflammatory cytokines, activating the autophagy signaling pathway, and inhibiting the expression of endoplasmic reticulum stress marker proteins.

Long-chain free fatty acids (FFAs) accumulation and oxidative toxicity is a major cause for several pathological conditions. The mechanisms underlying FFA cytotoxicity remain elusive. Here we show that palmitic acid (PA), the most abundant FFA in the circulation, induces S403 phosphorylation of SQSTM1/p62 (sequestosome 1) and its aggregation, which sequesters KEAP1 and activates the non-canonical SQSTM1-KEAP1-NFE2L2 antioxidant pathway. The PA-induced SQSTM1 S403 phosphorylation and aggregation are dependent on SQSTM1 K7-D69 hydrogen bond formation and dimerization in the Phox and Bem1 (PB1) domain, which facilitates the recruitment of TBK1 that phosphorylates SQSTM1 S403. The ubiquitin E3 ligase TRIM21 ubiquitinates SQSTM1 at the K7 residue and abolishes the PB1 dimerization, S403 phosphorylation, and SQSTM1 aggregation. TRIM21 is oxidized at C92, C111, and C114 to form disulfide bonds that lead to its oligomerization and decreased E3 activity. Mutagenizing the three C residues to S (3CS) abolishes TRIM21 oligomerization and increases its E3 activity. TRIM21 ablation leads to decreased SQSTM1 K7 ubiquitination, hence elevated SQSTM1 S403 phosphorylation and aggregation, which confers protection against PA-induced oxidative stress and cytotoxicity. Therefore, TRIM21 is a negative regulator of SQSTM1 phosphorylation, aggregation, and the antioxidant sequestration function. TRIM21 is oxidized to reduce its E3 activity that helps enhance the SQSTM1-KEAP1-NFE2L2 antioxidant pathway. Inhibition of TRIM21 May be a viable strategy to protect tissues from lipotoxicity resulting from long-chain FFAs.

Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

OBJECTIVE: As obesity and chronic kidney disease (CKD) remain a public health issue, we aim to elaborate on their complex relationship regarding pathogenetic mechanisms and therapeutic potential as well. The purpose of this review is to enhance our understanding of the interplay between obesity and CKD in order to timely diagnose and treat obesity-related CKD.
RESULTS: Obesity and CKD pose significant intertwined challenges to global health, affecting a substantial portion of the population worldwide. Obesity is recognized as an independent risk factor, intricately contributing to CKD pathogenesis through mechanisms such as lipotoxicity, chronic inflammation, and insulin resistance. Recent evidence highlights additional factors including hemodynamic changes and intestinal dysbiosis that exacerbate kidney dysfunction in obese individuals, leading to histologic alterations known as obesity-related glomerulopathy (ORG). This narrative review synthesizes current knowledge on the prevalence, pathophysiology, clinical manifestations, and diagnostic strategies of obesity-related kidney disease. Furthermore, it explores mechanistic insights to delineate current therapeutic approaches, future directions for managing this condition and controversies. By elucidating the multifaceted interactions between obesity and kidney health, this review aims to inform clinical practice and stimulate further research to address this global health epidemic effectively.

Type 2 diabetes mellitus (T2DM) is a widespread chronic disease characterized by persistent hyperglycemia, leading to severe complications such as diabetic cardiomyopathy and nephropathy, significantly affecting patient health and quality of life. The complex mechanisms underlying these complications include chronic inflammation, oxidative stress, and metabolic dysregulation. Diabetic cardiomyopathy, marked by structural and functional heart abnormalities, and diabetic nephropathy, characterized by progressive kidney damage, are major contributors to the increased morbidity and mortality associated with T2DM. AdipoRon, a synthetic adiponectin receptor agonist, has shown potential in preclinical studies for mimicking the beneficial effects of endogenous adiponectin, reducing inflammation and oxidative stress, and improving lipid metabolism and mitochondrial function. This systematic review evaluates the therapeutic potential of AdipoRon, focusing on its impact on diabetic cardiomyopathy and nephropathy. Through a comprehensive literature search and analysis, we highlight AdipoRon\'s role in ameliorating cardiovascular and renal complications in various animal models and cellular systems. The findings underscore the urgent need for translational clinical studies to validate AdipoRon\'s efficacy and safety in human populations, aiming to advance this promising therapeutic approach from experimental models to clinical application, potentially offering new hope for improved management of diabetic complications.

Lipid homeostasis is crucial for proper cellular and systemic functions. A growing number of studies confirm the importance of lipid homeostasis in diabetic kidney disease (DKD). Lipotoxicity caused by imbalance in renal lipid homeostasis can further exasperate renal injury. Large lipid deposits and lipid droplet accumulation are present in the kidneys of DKD patients. Autophagy plays a critical role in DKD lipid homeostasis and is involved in the regulation of lipid content. Inhibition or reduction of autophagy can lead to lipid accumulation, which in turn further affects autophagy. Lipophagy selectively recognizes and degrades lipids and helps to regulate cellular lipid metabolism and maintain intracellular lipid homeostasis. Therefore, we provide a systematic review of fatty acid, cholesterol, and sphingolipid metabolism, and discuss the responses of different renal intrinsic cells to imbalances in lipid homeostasis. Finally, we discuss the mechanism by which autophagy, especially lipophagy, maintains lipid homeostasis to support the development of new DKD drugs targeting lipid homeostasis.