Increased circulating FGF21 level predicts the burden of metabolic demands and risk of vascular diseases in adults with type 2 diabetes.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia and metabolic stress, involved in the stepwise development of cardiovascular complications. Fibroblast growth factor 21 (FGF21) is a novel hepatokine involved in regulating glucose and lipid metabolism, and has been linked to the prediction, treatment, and improvement of prognosis in multiple cardiovascular diseases (CVDs). The aim of this study is to explore the relationship between FGF21 levels and vascular diseases (VDs) including carotid atherosclerosis (CAS) and hypertension (HP) in patients with T2DM. METHODS: Baseline serum FGF21 was determined in a cross-sectional study of 701 patients with T2DM and 258 healthy control. RESULTS: The morbidity of CAS was increased in T2DM patients with HP as compared with those without (p < 0.001). The average serum FGF21 level of healthy was [123.9 (67.2-219.3)]. Baseline FGF21 was significantly higher in those who developed CAS or HP than in those who did not [305.9 (177.2-508.4) vs. 197.2 (129.7-308.3) pg/mL, p < 0.001]. In addition, an elevated serum FGF21 was observed in T2DM patients with HP and CAS than that of T2DM patients with CAS or HP [550.5 (312.6-711.3) vs. 305.9 pg/mL, p < 0.001]. Serum FGF21 levels were positively correlated with body mass index and carotid intima media thicknes (p < 0.05), the association remained significant after adjusting for age and T2DM duration. Furthermore, the multinomial logistic regression showed that serum FGF21 was independently associated with CAS and HP in patients with T2DM after adjustment for demographic and traditional VDs risk factors (p < 0.001). CONCLUSIONS: Baseline FGF21 is elevated in VDs during diabetes, changes of serum FGF21 levels were appropriately matched to metabolic stress. FGF21can be used as an independent predictor for diagnosing VDs and predicting prognosis.

Identification of exosomal mRNA, lncRNA and circRNA signatures in an osteoarthritis synovial fluid-exosomal study.

AIMS: Osteoarthritis (OA) is a common degenerative disease that is pathologically characterized by destruction of the joint matrix and reduction of articular chondrocytes, resulting in joint deformity and motor dysfunction. However, the molecular mechanisms governing this pathology have not been elucidated to date. METHODS: In this study, we determined the expression levels of lncRNAs, circRNAs, and mRNAs extracted from synovial exosomes of OA and control patients. A network of circRNA/lncRNA-miRNA-mRNA interactions was established using MiRanda and TargetScan software to explore OA pathogenesis. The exosomal lncRNA, circRNA and mRNA expression profiles of the OA and control groups were analysed using LC human competing endogenous RNA (ceRNA) microarrays. The differentially expressed genes were analysed to determine their potential roles in the pathogenesis of OA by bioinformatic analysis. RESULTS: There were 52 mRNAs, 196 lncRNAs and 98 circRNAs differentially expressed in synovial exosomes between osteoarthritis synovial and the control group. The final ceRNA network of lncRNAs and circRNAs exhibited a complex interaction between ncRNA and mRNA related to OA pathological mechanisms. An intersection analysis of the ceRNA network showed that 22 miRNAs, 45 lncRNAs, and 34 circRNAs enriched in the PI3K/Akt and autophagy pathways correlated with 7 mRNAs and may play important roles in OA pathological mechanisms. CONCLUSION: Our work analysed mRNA/lncRNA/circRNA expression and displayed the ceRNA network of lncRNAs and circRNAs to profile the pathogenesis of OA in synovial exosomes. The results of this study may help to elucidate the pathogenesis of OA and may provide important references for further research attempting to identify more effective targets for the diagnosis and therapy of OA.

Extracellular status of thrombospondin-2 in type 2 diabetes mellitus and utility as a biomarker in the determination of early diabetic kidney disease.

OBJECTIVE: Thrombospondin-2 (TSP-2) is a multifunctional matricellular glycoprotein correlated with glucose homeostasis, insulin sensitivity, and estimated glomerular filtration rate. Investigation of the association of TSP-2 with type 2 diabetes mellitus (T2DM) and the potential diagnostic value of serum TSP-2 for detecting early diabetic kidney disease (DKD) is needed. RESEARCH DESIGN AND METHODS: An enzyme-linked immunosorbent assay was used for detection serum TSP-2 levels in 494 Chinese T2DM subjects. The protein expression of TSP-2 in the kidney and other tissues were tested by western blotting. RESULTS: Serum TSP-2 levels in T2DM subjects were significantly higher than in healthy individuals. Serum TSP-2 correlated positively with triglycerides, serum uric acid, creatinine, platelets, and urinary albumin-to-creatinine ratio (UACR), but negatively with estimated glomerular filtration rate, after adjusting for age, sex, and T2DM duration. Logistic regression analysis demonstrated an independent association between serum TSP-2 and early DKD. Furthermore, the high UACR identified at risk of early DKD increased significantly from 0.78 (95%CI 0.73-0.83) to 0.82 (95%CI 0.77-0.86, p < 0.001) when added to a clinical model consisting of TSP-2 and age. In db/db mice, serum TSP-2 levels were elevated. TSP-2 expression was markedly increased in the kidney tissue compared with that in db/m and m/m mice. Furthermore, serum TSP-2 expression correlated well with UACR in mice. CONCLUSIONS: TSP-2 is a novel glycoprotein associated with early DKD in patients with T2DM. The paradoxical increase of serum TSP-2 in T2DM individuals may be due to a compensatory response to chronic inflammatory and renal vascular endothelial growth, warranting further investigation.

FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway.

Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4 )-induced ALI. We established CCl4 -induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro-inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor-alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule-associated protein light chain-3 beta (LC3 II) and autophagy key molecule coiled-coil myosin-like BCL2-interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4 -treated wild-type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti-SIRT1 lentit-RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1-mediated autophagy.

Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1-autophagy signalling pathway.

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity, alleviates the process of acute pancreatitis (AP). However, its mechanism remains elusive. The pathological and physiological characteristics of FGF21 are observed in both patients with AP and cerulein-induced AP models, and the mechanisms of FGF21 in response to AP are investigated by evaluating the impact of autophagy in FGF21-treated mice and cultured pancreatic cells. Circulating levels of FGF21 significantly increase in both AP patients and cerulein-induced AP mice, which is accompanied by the change of pathology in pancreatic injury. Replenishment of FGF21 distinctly reverses cerulein-induced pancreatic injury and improves cerulein-induced autophagy damage in vivo and in vitro. Mechanically, FGF21 acts on pancreatic acinar cells to up-regulate Sirtuin-1 (Sirt1) expression, which in turn repairs impaired autophagy and removes damaged organs. In addition, blockage of Sirt1 accelerates cerulein-induced pancreatic injury and weakens the regulative effect in FGF21-activated autophagy in mice. These results showed that FGF21 protects against cerulein-induced AP by activation of Sirtuin-1-autophagy axis.

Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner.

Fibroblast growth factor 21 (FGF21) is important in glucose, lipid homeostasis and insulin sensitivity. However, it remains unknown whether FGF21 is involved in insulin expression and secretion that are dysregulated in type 2 diabetes mellitus (T2DM). In this study, we found that FGF21 was down-regulated in pancreatic islets of db/db mice, a mouse model of T2DM, along with decreased insulin expression, suggesting the possible involvement of FGF21 in maintaining insulin homeostasis and islet ß-cell function. Importantly, FGF21 knockout exacerbated palmitate-induced islet ß-cell failure and suppression of glucose-stimulated insulin secretion (GSIS). Pancreatic FGF21 overexpression significantly increased insulin expression, enhanced GSIS, improved islet morphology and reduced ß-cell apoptosis in db/db mice. Mechanistically, FGF21 promoted expression of insulin gene transcription factors and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, the major regulators of insulin secretion, as well as activating phosphatidylinositol 3-kinase (PI3K)/Akt signaling in islets of db/db mice. In addition, pharmaceutical inhibition of PI3K/Akt signaling effectively suppressed FGF21-induced expression of insulin gene transcription factors and SNARE proteins, suggesting an essential role of PI3K/Akt signaling in FGF21-induced insulin expression and secretion. Taken together, our results demonstrate a protective role of pancreatic FGF21 in T2DM mice through inducing PI3K/Akt signaling-dependent insulin expression and secretion.

CXCL16 deficiency attenuates diabetic nephropathy through decreasing oxidative stress and inflammation.

Soluble C-X-C chemokine ligand 16 (CXCL16) is related to the inflammatory response in liver injury and involved in the pathogenesis of renal dysfunction in diabetes patients. However, the exact role of elevated CXCL16 in diabetic nephropathy (DN) remains unclear. In this study, we investigated the role of CXCL16 in streptozcin (STZ)-induced diabetic nephropathy (DN) in mice. The results showed that fasting blood glucose (FBG) and 24 h urinary protein, triglyceride, and cholesterol levels increased in diabetic mice, and these changes were partially ameliorated in CXCL16 KO mice. Meanwhile, the results also showed that ROS generation was suppressed and the expression levels of inflammatory factors and infiltration factors were inhibited both in vivo and in vitro using DN models. In addition, the total AKT protein and p-AKT levels were decreased in CXCL16-depleted HK-2 cells that were treated with LPS. These findings suggest that the CXCL16 gene product promotes inflammatory factors and cell infiltration factors, and inhibits the expression of antioxidant factors to accelerate the development of DN, and CXCL16 deficiency attenuates DN may be involved in the AKT signaling pathway.

Hepatic CXCL16 is increased in gallstone accompanied with liver injury.

BACKGROUND AND AIMS: This study aimed to investigate the relationship between circulating soluble C-X-C chemokine ligand 16 (CXCL16) levels and clinical characteristics of gallstone. METHODS: 93 subjects including 53 subjects with gallstone, 25 subjects with nonalcoholic fatty liver disease (NAFLD), and 40 control subjects were recruited. All gallstone subjects underwent ultrasounds to confirm the gallstone patients. Serum CXCL16 levels and other clinical and biochemical parameters in all subjects were obtained based on standard clinical examination methods. Liver tissues from patients with gallstone undergoing cholecystotomy and healthy subjects were also used to determine the hepatic CXCL16 profiles by IHC staining and real-time quantitative PCR. RESULTS: Serum CXCL16 levels were significantly increased in patients with gallstone and NAFLD as compared to healthy controls (P < 0·001). Hepatic CXCL16 mRNA and protein levels were also significantly increased in gallstone patients following with elevation of hepatic triglycerides and free fatty acid concentration, as compared to those in healthy subjects (P < 0·001). Otherwise, serum CXCL16 levels positively correlated with nonalcoholic fatty liver disease (NAFLD), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT) and direct bilirubin (P < 0·05), but negatively with total protein and albumin after adjustment with age and gender. Multiple stepwise regression analyses indicated that CXCL16 was independently associated with AST, NAFLD and albumin (P < 0·05, respectively). CONCLUSIONS: Serum CXCL16 levels are significantly increased in patients with gallstone, and are independently associated with liver injury in Chinese population, suggesting that CXCL16 may be a biomarker of liver injury in subjects with gallstone or NAFLD.

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice.

The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21-deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis.

CXCL16 deficiency attenuates acetaminophen-induced hepatotoxicity through decreasing hepatic oxidative stress and inflammation in mice.

Chemokine C-X-C ligand 16 (CXCL16), a single-pass Type I membrane protein belonging to the CXC chemokine family, is related to the inflammatory response in liver injury. In present study, we investigated the pathophysiological role of CXCL16, a unique membrane-bound chemokine, in acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were injected with APAP, and blood and tissue samples were harvested at different time points. The serum high-mobility group box 1 and CXCL16 levels were quantified by sandwich immunoassays. The liver tissue sections were stained with hematoxylin-eosin or with dihydroethidium staining. The expressions of CXCL16 and other cytokines were examined by real-time polymerase chain reaction. Ly6-B, p-jun N-terminal kinase (p-JNK), and JNK expressions were measured by western blot analysis. Intracellular glutathione, reactive oxygen species, and malondialdehyde levels were also measured. APAP overdose increased hepatic CXCL16 mRNA and serum CXCL16 protein levels. CXCL16-deficient mice exhibited significantly less liver injury and hepatic necrosis, as well as a lower mortality than wild-type (WT) mice in response to APAP-overdose treatment. APAP elevated the production of oxidative stress and decreased mitochondrial respiratory chain activation in WT mice, which was strongly reversed in CXCL16-knockout mice. In addition, CXCL16 deficiency inhibited the neutrophil infiltration and the production of proinflammatory cytokines triggered by APAP-overdose treatment. Our study revealed that CXCL16 is a critical regulator of liver immune response to APAP-induced hepatotoxicity, thus providing a potential strategy for the treatment of drug-induced acute liver failure by targeting CXCL16.

Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive. METHODS AND RESULTS: The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2. CONCLUSIONS: FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.

Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2.

BACKGROUND & AIMS: Inflammatory cell infiltration in the liver is a hallmark of non-alcoholic steatohepatitis (NASH). However, the pathological events which trigger the infiltration of inflammatory cells to mediate NASH pathogenesis remains poorly understood. This study aims to investigate the role of neutrophil-derived lipocalin 2 (LCN2) in mediating the transition from simple steatosis to NASH. METHODS: Animal models of NASH were induced by high fat high cholesterol (HFHC) diet and methionine- and choline-deficient (MCD) diet in LCN2 knockout mice and wild-type controls. RESULTS: Circulating levels of LCN2 and its hepatic expression were markedly increased in both murine models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of LCN2. In contrast, chronic infusion of recombinant LCN2 exacerbated diet-induced liver injury, inflammation and macrophage accumulation in a neutrophil-dependent manner. Primary mouse neutrophils lacking LCN2 exhibited a defective migration capacity, which can be reversed by replenishment with recombinant LCN2. Mechanistically, LCN2 induced the expression of the chemokine (C-X-C motif) receptor 2 (CXCR2), thereby leading to activation of ERK1/2 and production of proinflammatory chemokines. LCN2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice. CONCLUSIONS: These findings demonstrated that LCN2 acts as a central mediator to facilitate the crosstalk between neutrophils and hepatic macrophages via induction of the chemokine receptor CXCR2, thereby exacerbating steatohepatitis. LAY SUMMARY: Lipocalin-2 levels in blood and the liver were markedly increased in both mouse models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils in the liver. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of lipocalin-2, but was augmented by chronic infusion of recombinant lipocalin-2. Lipocalin-2 induced the expression of the chemokine receptor CXCR2, thereby leading to activation of the mitogen-activated protein (MAP) kinase ERK1/2 and production of proinflammatory chemokines. Lipocalin-2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice.

Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose causes hepatic necrosis and acute liver injury by inducing mitochondrial dysfunction and damage. Although the biochemical pathways that mediate APAP-induced hepatotoxicity have been well studied, the body's defense mechanism to attenuate this disease remains elusive. This study investigated the roles of adiponectin, an adipocyte-secreted adipokine with pleiotropic protective effects against obesity-related metabolic dysfunction, in the pathogenesis of APAP-induced liver injury in mice. METHODS: Adiponectin knockout (ADN KO) and C57 wild type mice were treated with an overdose of APAP, followed by histological and biochemical evaluation of liver injury and activation of autophagy. The mechanism of adiponectin in APAP-induced hepatocytic toxicity was also explored in primary cultured hepatocytes. RESULTS: APAP overdose triggers a marked accumulation of adiponectin in injured liver tissues. ADN KO mice exhibit severely exacerbated mitochondrial dysfunction and damage, oxidative stress and necrosis and much higher mortality in response to APAP overdose, whereas these changes are reversed by a single injection of adiponectin. Mechanistically, adiponectin induces autophagosome formation by AMP-activated protein kinase (AMPK)-dependent activation of the Unc-51-like kinase 1, consequently leading to the removal of damaged mitochondria from hepatocytes. The protective effects of adiponectin against APAP-induced mitochondrial damage, oxidative stress and necrosis are abrogated by blockage of AMPK or pharmacological inhibition of autophagy. CONCLUSIONS: Our findings suggest that the APAP-induced accumulation of adiponectin in liver tissues serves as an adaptive mechanism to ameliorate hepatotoxicity by promoting autophagy-mediated clearance of damaged mitochondria. Adiponectin agonists may represent a promising therapy for the drug-induced acute liver failure.

Adipose c-Jun NH2-terminal kinase promotes angiotensin II-induced and deoxycorticosterone acetate salt-induced hypertension and vascular dysfunction by inhibition of adiponectin production and activation of SGK1 in mice.

BACKGROUND: Adipose c-Jun NH2-terminal kinase 1/2 (JNK1/2) is a central mediator involved in the development of obesity and its complications. However, the roles of adipose JNK1/2 in hypertension remain elusive. Here we explored the role of adipose JNK1/2 in hypertension. METHODS AND RESULTS: The roles of adipose JNK1/2 in hypertension were investigated by evaluating the impact of adipose JNK1/2 inactivation in both angiotensin II (Ang II)-induced and deoxycorticosterone acetate (DOCA) salt-induced hypertensive mice. Specific inactivation of JNK1/2 in adipocytes significantly alleviates Ang II-induced and DOCA salt-induced hypertension and target organ damage in mice. Interestingly, such beneficial effects are also observed in hypertensive mice after oral administration of JNK1/2 inhibitor SP600125. Mechanistically, adipose JNK1/2 acts on adipocytes to reduce the production of adiponectin (APN), then leads to promote serum and glucocorticoid-regulated kinase 1 (SGK1) phosphorylation and increases epithelial Na + channel α-subunit (ENaCα) expression in both renal cells and adipocytes, respectively, finally exacerbates Na + retention. In addition, chronic treatment of recombinant mouse APN significantly augments the beneficial effects of adipose JNK1/2 inactivation in DOCA salt-induced hypertension. By contrast, the blood pressure-lowering effects of adipose JNK1/2 inactivation are abrogated by adenovirus-mediated SGK1 overexpression in Ang II -treated adipose JNK1/2 inactivation mice. CONCLUSION: Adipose JNK1/2 promotes hypertension and targets organ impairment via fine-tuning the multiorgan crosstalk among adipose tissue, kidney, and blood vessels.

Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti.

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD), especially advanced metabolic dysfunction-associated steatohepatitis (MASH), have an increased risk of cardiovascular diseases (CVDs). Whether CVD events will, in turn, influence the pathogenesis of MASLD remains unknown. Here, we show that myocardial infarction (MI) accelerates hepatic pathological progression of MASLD. Patients with MASLD who experience CVD events after their diagnosis exhibit accelerated liver fibrosis progression. MI promotes hepatic fibrosis in mice with MASH, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to damaged liver tissues. These adverse effects are significantly abrogated when deleting these cells. Meanwhile, MI substantially increases circulating and cardiac periostin levels, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of MASH. These preclinical and clinical results demonstrate that MI alters systemic homeostasis and upregulates pro-fibrotic factor production, triggering cross-disease communication that accelerates hepatic pathological progression of MASLD.

2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition.

A growing proportion of the global adult and pediatric populations are currently affected by nonalcoholic steatohepatitis (NASH), leading to rising rates of liver fibrosis and hepatocellular carcinoma without effective pharmacotherapy. Here, we investigated whether 2-geranyl-1-methoxyerythrabyssin II (GMET), isolated from Lespedeza bicolor, could alleviate lipid accumulation and inflammatory responses in a NASH model. GMET exhibited potent in vitro and in vivo effects against lipid accumulation and attenuated inflammatory responses without cytotoxicity. Mechanistically, GMET inhibits acetyl-CoA carboxylase (ACC), sterol regulatory element-binding proteins-1c (SREBP1), and mammalian target of rapamycin (mTOR), and activates PPARα by activating AMP-activated kinase (AMPK), leading to the alleviation of lipid accumulation. In addition, GMET suppresses the NF-κB pathway by activating AMPK and inhibiting the activated protein kinase B (AKT)/IκB-kinase (IKK) pathway, leading to the inhibition of the inflammatory response in hepatocytes. All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

Fibroblast growth factor 21 resistance is associated with body shape in patients with type 2 diabetes complicating hypertension.

Objectives: Obesity, especially abdominal obesity, increases the prevalence of metabolic and cardiovascular disease (CVD). Fibroblast growth factor 21 (FGF21) has been identified as a critical regulator playing a therapeutic role in diabetes and its complications. This study aims to evaluate the relationship between serum FGF21 levels and body shape parameters in patients with hypertension (HP) and type 2 diabetes mellitus (T2DM). Methods: Serum FGF21 levels were determined in 1,003 subjects, including 745 patients with T2DM, and 258 individuals were selected as a healthy control in this cross-sectional study. Results: Serum FGF21 levels were significantly higher in T2DM patients with HP than those without [534.9 (322.6-722.2) vs. 220.65 (142.8-347.55) pg/ml, p < 0.001], and levels in both of these two groups were significantly increased compared with that of healthy control [123.92 (67.23-219.32) pg/ml, all p < 0.001]. These differences were also observed in body shape parameters, including weight, waistline, body mass index (BMI), body shape index (ABSI), and the percentage of abdominal obesity. Serum FGF21 levels in T2DM patients were positively correlated with body shape parameters, including weight, waistline, neck circumference, BMI, ABSI, percent of abdominal obesity, and triglyceride, while negatively with estimated glomerular filtration rate (all p < 0.01). The significance remained stable when adjusted for age and T2DM duration. In addition, both serum FGF21 concentrations and waistline were independently associated with HP in T2DM patients after the adjustment for risk factors (all p < 0.05). ROC analysis for FGF21 levels of 745 patients with T2DM identified 411.33 pg/ml as an optimal cut-off point to predict HP, with a sensitivity and specificity of 66.0% and 84.9%, respectively. Conclusions: FGF21 resistance occurs in patients of HP in T2DM, and positively correlates with body shape parameters (especially waistline and BMI). High levels of FGF21 may be a compensatory reaction to offset HP.

Serum FGF21 Levels Predict the MACE in Patients With Myocardial Infarction After Coronary Artery Bypass Graft Surgery.

Objectives: Prognosis evaluation in myocardial infarction (MI) patients with major adverse clinical events (MACE) who have undergone coronary artery bypass graft (CABG) is greatly important to identify high-risk patients. Elevated metabolic hormone fibroblast growth factor 21 (FGF21) is associated with the risk of MI. The aim of this study is to assess the relationship between FGF21 and the incidence of MACE in patients with MI after CABG surgery. Methods: Patients with three-vessel disease who were scheduled for first-time isolated CABG were enrolled in this project and underwent to evaluate the incidence of MACE during 48 h after CABG surgery, as well as to collect serum samples for FGF21 levels in both preoperative- and postoperative-CABG (pre-CABG and post-CABG). Results: A total of 265 patients with MI undergoing CABG were enrolled in this study, 21 patients experienced MACE during the 48 h after CAGB surgery. Serum FGF21 levels of patients with MACE at post-CABG were significantly higher than that in patients without MACE [553.7 (433.6) vs. 291.7 (334.4), p < 0.001]. Furthermore, among 81 individuals of these 265 patients, a lower level of FGF21 in preoperative-CABG (pre-CABG) and a higher level of FGF21 at postoperative-CABG (post-CABG) were observed in MI patients with MACE as compared to those without MACE respectively [ (275.0 (260.4) vs. 410.3 (420.7), p = 0.049; 550.7 (519.9) vs. 370.6 (441.2), p = 0.031]. In addition, serum FGF21 levels of MI patients with MACE at post-CABG were significantly increased compared with the baseline levels in pre-CABG [550.7 (519.9) vs.275.0 (260.4) p < 0.001]. However, these profiles were not observed in patients without MACE [410.3 (420.7) vs. 370.6 (441.2), p=0.2137]. Logistic regression analysis demonstrated that both serum FGF21 and CK-MB levels at post-CABG were independently associated with the incidence of MACE in patients with MI after CABG surgery. Finally, ROC analysis for FGF21 levels of 265 MI patients at post-CABG identified 455.4 pg/ml as an optimal cut-off value to predict MACE, with a sensitivity and specificity of 91.7 and 68.4% respectively. Conclusion: Serum FGF21 levels at post-CABG are independently associated with the incidence of MACE in patients with MI who have undergone CABG. Measurement of FGF21 may help distinguish patients with MI at a high risk of MACE after CABG surgery.

Serum Lipocalin-2 Levels Are Increased and Independently Associated With Early-Stage Renal Damage and Carotid Atherosclerotic Plaque in Patients With T2DM.

Objectives: Diabetic nephropathy (DN), one of the major complications of diabetes mellitus, is the major cause of end-stage renal failure that finally increases the risk of cardiovascular disease and mortality. The aim of this study is to explore the relationship between serum lipocalin-2 (LCN-2) levels and DN and carotid atherosclerotic plaque (CAP) in patients with type 2 diabetes mellitus (T2DM). Methods: We have performed a prospective study of 749 T2DM patients with or without DN. Blood samples were collected and used to test serum LCN-2 levels, renal function, as well as biochemical parameters. CAP in these subjects was determined by ultrasonography. Results: In these 749 subjects with T2DM, an increased morbidity of CAP was observed in T2DM patients with DN as compared with those without this complication (P < 0.05). Interestingly, serum LCN-2 levels were significantly increased in T2DM patients with DN or CAP compared with T2DM alone [97.71 (71.49-130.13) vs. 77.29 (58.83-115.05) ng/ml, P < 0.001]. In addition, serum LCN-2 levels in T2DM patients with DN and CAP were significantly higher than that of T2DM patients with DN or CAP [131.37 (101.43-182.04) vs. 97.71(71.49-130.13) ng/ml, P < 0.001]. Furthermore, serum LCN-2 levels were positively correlated with hemoglobin A1c, systolic blood pressure, hypertension, CAP, and DN, as well as renal function factors including uric acid, creatinine, the estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio, respectively (P < 0.05), but negatively correlated with HDL-c (P < 0.05). The multinomial logistic regression analysis showed that serum LCN-2 was independently associated with DN and CAP in patients with T2DM after the adjustment for risk factors (P < 0.001). Conclusions: Early-stage renal damage is a risk factor associated with the incidence of CAP in patients with T2DM. Serum LCN-2 is significantly increased and associated with early-stage renal damage and the incidence of CAP in patients with T2DM.