Apoptosis plays a major role in fatty liver disease. High-fat diets are related to the onset of fatty liver disease and hepatic oxidant-antioxidant imbalance. Curcumin and capsaicin are somewhat beneficial in reducing hepatic triglycerides; this is most likely because they are known to downregulate reactive oxygen species (ROS) and apoptosis. The aim of this study was to investigate the effects of curcumin and capsaicin on apoptosis through the oxidative effect in an animal model of fatty liver disease. Male Sprague Dawley rats were fed a normal control diet, a high-fat diet (HFD; 60% of total calories from fat), a HFD+curcumin (1.5 g curcumin/kg HFD), a HFD+capsaicin (0.15 g capsaicin/kg HFD), or a HFD+curcumin+capsaicin (1.5 g curcumin and 0.15 g capsaicin/kg HFD). Liver lysate levels of BAX, Bcl-2 and caspase-3 were determined via immunoblotting. Caspase-3 activity was measured with a colorimetric caspase-3 measurement kit. Total antioxidant status (TAS) and total oxidant status (TOS) were assayed using commercial kits. The generation of hepatic ROS was measured with fluorimetry. Fragmentation of DNA was detected using the TUNEL method. High-fat diet caused increased expression of BAX and caspase-3, as well as increased TOS and caspase-3 activity, but decreased expression of Bcl-2. HFD+curcumin+capsaicin caused decreased BAX, caspase-3, TOS, and ROS levels as compared to HFD, but increased TAS and Bcl-2. A HFD +curcumin+capsaicin also decreased the number of TUNEL-positive cells. These results suggest that supplementation with curcumin and capsaicin balances the hepatic oxidant-antioxidant status and may have a protective role in the apoptotic process in an HFD-induced fatty liver model.

The effects of curcumin on mast cell chymase activity in fatty liver and serum fetuin-A levels in rats fed a high-fat diet (HFD) were investigated. Male Sprague-Dawley rats received HFD (60% of total calories from fat) and 1 g curcumin/kg HFD for 16 weeks. Hepatic chymase activity was determined using spectrophotometric analysis while liver lipid levels were measured using colorimetric methods and serum fetuin-A, insulin, leptin, and adiponectin levels were detected using commercial enzyme-linked immunosorbent assay kits. Hepatic fat accumulation and fibrotic changes were ameliorated with curcumin treatment. Curcumin significantly reduced hepatic lipids, chymase activity, and serum fetuin-A levels. Decreased serum leptin and augmented adiponectin levels were also observed. These findings suggest that curcumin attenuated hepatic fat accumulation and regulated adipokine levels. The reduction of liver chymase activity and serum fetuin-A levels may also contribute to the beneficial effects of curcumin in fatty liver disease induced inflammatory status. Curcumin (diferuloylmethane), which is extracted from the dried root of the rhizome Curcuma longa, is a popular dietary spice (turmeric) in Asia and used in curry. Turmeric is widely used as food component, flavoring agent, and colorant. This research revealed that dietary curcumin treatment reduces hepatic fat accumulation, ameliorates liver damage, and inflammation related to fat storage. Therefore, curcumin may be a potential protective agent in the prevention of fatty liver disease and the anti-inflammatory capacity of curcumin may reveal a beneficial application in medicine and also food technology.

Fetuin-A (FetA) is a glycoprotein primarily synthesized in hepatocytes, but recent studies have demonstrated that it is also synthesized in adipose tissue, classifying it as both a hepatokine and an adipokine. FetA has been shown to play a role in the regulation of glucose and lipid metabolism, thereby controlling overall body homeostasis. Elevated serum FetA levels have been reported in obesity, and this increase has been associated with insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Therefore, investigating the molecular mechanisms underlying the variations of FetA in obesity and obesity-related metabolic diseases is crucial for the development of preventive strategies. Studies examining the molecular pathways involved in the relationship between FetA, adipose tissue, IR, and T2DM have shown that deviations in the expression of transcription factors such as nuclear factor erythroid-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) in pancreatic, adipose, and liver cells contribute to the increase in FetA and the development of IR and/or T2DM. Consequently, future studies aimed at suppressing transcription factors in the signaling pathways that increase FetA expression, and identifying new agents that can regulate FetA secretion, could be therapeutically beneficial in treating obesity and obesity-related complications.

Objectives: This study aimed to investigate serum fetuin-A (FetA) and adiponectin levels, the FetA/adiponectin ratio (FAR), and their roles in inflammation and insulin resistance in overweight individuals. Instead of evaluating FAR as a predictive biomarker, this study aimed to explore its association with metabolic parameters in this population. Materials: The study included 57 participants aged 24–56 years, divided into control (BMI<25 kg/m ² , n=27) and overweight (BMI 25–30 kg/m ² , n=30) groups. Anthropometric measurements and body composition analyses were performed after a 12-h fasting period. Serum FetA, adiponectin, progranulin, and CTRP-3 levels were measured using ELISA. Insulin resistance was assessed using the HOMA-IR index. Statistical analyses included Mann–Whitney U tests, correlation analyses, and ROC curve analysis. Results: Overweight individuals showed significantly higher waist circumference, body fat mass, and HOMA-IR compared to controls, while adiponectin levels were significantly lower (p=0.006). The FAR was elevated in the overweight group (p=0.023) and positively correlated with BMI, body fat mass, and HOMA-IR (p<0.05). Progranulin and CTRP-3 levels showed no significant differences between groups, but a negative correlation between these two adipokines was observed. ROC analysis revealed an optimal FAR cut-off of 40.5 for predicting increased BMI, with 60 % sensitivity and 80 % specificity. Conclusions: The findings suggest that FAR is associated with insulin resistance and metabolic parameters in overweight individuals. Although promising, its clinical utility as a diagnostic biomarker requires further investigation.

Metabolic inflammation, a state of chronic low-grade inflammation linked to insulin resistance, plays a central role in the development of obesity-related conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disorders. In recent years, two molecules have gained significant prominence in this field, owing to their mechanistic involvement in metabolic inflammation and insulin resistance: fetuin-A (FetA), aliver-derived hepatokine, and chymase, a serine protease released from mast cells. Although they arise from distinct biological sources, they converge on overlapping inflammatory and metabolic pathways. FetA acts as an endogenous ligand for Toll-like receptor 4 (TLR4), activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, driving proinflammatory cytokine release, and impairing insulin signaling. Chymase, on the other hand, generates angiotensin II and activates transforming growth factor-β (TGF-β), thereby promoting oxidative stress, fibrosis, and secondary metabolic dysfunction. This review proposes a conceptual dual-target framework in which FetA and chymase are considered complementary, rather than independent, mediators of metabolic inflammation. Importantly, this framework is not intended to supersede other established pathways implicated in metabolic inflammation, but rather to provide an integrative perspective that complements existing hepatokine and immune-centered models. Their convergence on NF-κB and TGF-β signaling pathways highlights shared mechanistic nodes within metabolic inflammation. Accordingly, the emphasis of this review is on mechanistic integration within metabolic inflammation, rather than on immediate therapeutic innovation or clinical translation.

Metabolic diseases are characterized by a complex interplay between metabolic dysregulation and chronic low-grade inflammation. Fetuin-A (FetA), a liver-derived hepatokine, has emerged as a key mediator linking these processes through its pro-inflammatory and insulin resistance-promoting effects. Accumulating evidence indicates that FetA not only serves as a biomarker but also actively contributes to disease pathogenesis by modulating multiple signaling pathways. In this review, we present an overview of the molecular mechanisms underlying FetA-induced suppression of peroxisome proliferator-activated receptor (PPAR) signaling, a central regulator of metabolic homeostasis. Emerging evidence suggests that FetA may promote Toll-like receptor 4 (TLR4)-mediated inflammation, activate nuclear factor kappa B (NF-κB) signaling, suppress key energy regulators such as Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), and inhibit PPAR activity through Wnt and extracellular signal-regulated kinase (ERK) pathways. These interconnected mechanisms may contribute to impaired lipid metabolism, increased insulin resistance, and metabolic inflammation. Furthermore, we highlight the role of FetA glycosylation, particularly fucosylation, as a regulatory layer influencing its biological activity. Fucosylated FetA may more effectively activate TLR4 signaling and suppress PPAR activity, suggesting functional heterogeneity among glycoforms. Overall, the FetA–PPAR interaction may represent a key mechanistic link between metabolic inflammation and disease progression.