Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies ranging from uncomplicated hepatic fat accumulation to a state of lobular inflammation and hepatocyte ballooning, known ...as non-alcoholic steatohepatitis (NASH). Currently, there are no reliable biomarkers or effective therapeutic options established for NAFLD. Nevertheless, there are several molecular targets in the pipeline, of which fibroblast growth factor 21 (FGF21) is one. FGF21 is secreted primarily from liver and has a plethora of metabolic functions. Pre-clinical and epidemiological studies indicate a relationship between circulating FGF21 levels and hepatic fat content in both mice and humans. Moreover, animal studies have clearly shown that aberrant FGF21 signalling is a key pathological step in the development and progression of NAFLD. A recent Phase II clinical trial demonstrated that administration of an FGF21 analogue significantly reduced hepatic fat in subjects with NASH. As such, FGF21 provides a novel target for future biomarker and therapeutic studies. This review appraises preclinical data to outline the current understanding of FGF21 function in both normal hepatic function and NAFLD. Epidemiological evidence is explored to delineate the relationship between circulating FGF21 levels and NAFLD in humans. Finally, we review the therapeutic effects of FGF21 in the treatment of NAFLD.
•FGF21 is a key regulator of hepatic glucose and lipid metabolism.•FGF21 resistance increases fatty acid supply to the liver and reduces fatty acid utilisation.•Hepatic fatty acid accumulation promotes lipotoxicity.•Circulating FGF21 levels are elevated in patients with NAFLD.•FGF21 mimetics are effective at reducing hepatic steatosis and inflammation.
Abstract
Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can ...detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading.
Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium ...butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator-activated receptor-α function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.
The choroid layer is a vascular layer in human retina and its main function is to provide oxygen and support to the retina. Various studies have shown that the thickness of the choroid layer is ...correlated with the diagnosis of several ophthalmic diseases. For example, diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. Despite contemporary advances, automatic segmentation of the choroid layer remains a challenging task due to low contrast, inhomogeneous intensity, inconsistent texture and ambiguous boundaries between the choroid and sclera in Optical Coherence Tomography (OCT) images. The majority of currently implemented methods manually or semi-automatically segment out the region of interest. While many fully automatic methods exist in the context of choroid layer segmentation, more effective and accurate automatic methods are required in order to employ these methods in the clinical sector. This paper proposed and implemented an automatic method for choroid layer segmentation in OCT images using deep learning and a series of morphological operations. The aim of this research was to segment out Bruch's Membrane (BM) and choroid layer to calculate the thickness map. BM was segmented using a series of morphological operations, whereas the choroid layer was segmented using a deep learning approach as more image statistics were required to segment accurately. Several evaluation metrics were used to test and compare the proposed method against other existing methodologies. Experimental results showed that the proposed method greatly reduced the error rate when compared with the other state-of-the-art methods.
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•Rutin showed the most potent AGEs inhibitory capacity in both food and HepG2 cell models.•Rutin mitigated glucose metabolism disorders induced by AGEs in HepG2 cells.•Rutin ...alleviated AGEs-induced insulin resistance via SOCS3/IRS1 and PI3K/AKT pathways.•PI3K/AKT pathway played an important role in enhancing insulin sensitivity in response to rutin.
The accumulation of advanced glycosylation end products (AGEs) from food in the body disrupts normal physiological insulin activity and causes insulin resistance. This study compared the effects of ten types of polyphenols on AGEs production in both chemical and food models. It also investigated the impact of polyphenols on AGEs-induced insulin resistance in HepG2 cell models. Results showed that luteolin had the strongest inhibitory effect on fluorescent AGEs in the three chemical models. Rutin exhibited the most potent capacity to inhibit AGEs in biscuit models. Moreover, rutin alleviated the glucose metabolism disorders induced by representative AGEs (methylglyoxal-modified bovine serum albumin, MGO-BSA) in HepG2 cells. Mechanistic studies revealed that rutin could inhibit the phosphorylation of insulin receptor substrate 1 (IRS1) and the activity of suppressor of cytokine signaling 3 (SOCS3), while activating the phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) to alleviate the MGO-BSA-induced insulin resistance in HepG2 cells.
Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and ...cirrhosis.
Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation.
ApoE(-/-)/TLR4(mut) mice and ApoE(-/-)/TLR4 wild-type mice (ApoE(-/-)/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE(-/-)) strain with TLR4-mutant (TLR4(mut)) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity.
ApoE(-/-)/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE(-/-)/TLR4(mut) mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE(-/-)/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE(-/-)/TLR4(mut) mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice.
These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.
Background & Aims Fibroblast growth factor 21 (FGF21), a hormone predominantly secreted by the liver, has been shown to be positively associated with the severity of non-alcoholic fatty liver disease ...(NAFLD) in cross-sectional studies. We investigated the prospective association of FGF21 with NAFLD development in a 3-year prospective study involving a population-based cohort comprising 808 Chinese subjects. Methods Serum FGF21 levels at baseline and follow-up were measured using an enzyme-linked immunosorbent assay. Independent predictors of NAFLD development were identified using multiple logistic regressions. The predicting accuracy of the models was evaluated using area under the receiver-operating characteristic (ROC) curves (AUCs). Results In subjects who had progressed to NAFLD, the baseline FGF21 concentration (319.12 pg/ml 172.65, 518.78) was significantly higher than that in subjects who did not develop NAFLD (199.10 pg/ml 123.56, 322.80) ( p <0.001). At follow-up, significant increase of FGF21 level was observed in those subjects who developed NAFLD ( p < 0.05). Baseline FGF21 was an independent predictor of NAFLD (OR: 7.102 95% CI 2.488–20.270; p < 0.001), together with body mass index (BMI) (OR: 1.489 95% CI 1.310–1.691; p < 0.001). The ROC-AUC was 0.816 (95% CI 0.766–0.867) for the FGF21 Model, which was calculated with FGF21 and BMI. FGF21 Model <0.13 can be used to rule out (sensitivity = 85.71%, negative likelihood ratio = 0.23) and ⩾0.30 can be rule in (specificity = 86.34%, positive likelihood ratio = 3.66) ultrasonography-diagnosed NAFLD after 3 years. Conclusions High serum FGF21 concentration was an independent predictor of NAFLD in humans. The FGF21 Model and its cut-offs may be useful for early diagnosis and intervention of NAFLD.
Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight. Several studies have linked the gut microbiome to ...obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear. A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D. The abundance of Akkermansia muciniphila (A. muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D. Its abundance correlates inversely with serum 3β‐chenodeoxycholic acid (βCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations. The supplementation with A. muciniphila is sufficient to protect mice against high sucrose‐induced impairment of glucose intolerance by decreasing βCDCA and increasing insulin secretion and FGF15/19. Furthermore, βCDCA inhibits insulin secretion and FGF15/19 expression. These findings suggest that decreased abundance of A. muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes.
Intestinal Akkermansia muciniphila is depleted in lean individuals with type 2 diabetes, who have increased 3β‐chenodeoxycholic acid (βCDCA), reduced insulin secretion and fibroblast growth factor 19 (FGF19) expression. A. muciniphila treatment in mice modulates βCDCA levels, stimulates insulin secretion and FGF19 expression, leading to improved glucose metabolism. The way is paved fornew therapeutic options for diabetes prevention or treatment.
Background FGF21 (fibroblast growth factor 21), a novel hepatokine regulating lipid metabolism, has been linked to atherosclerotic disease. However, whether this relationship exists in patients ...without nonalcoholic fatty liver disease is unclear. We assessed the association between serum FGF21 levels and atherosclerosis in patients without nonalcoholic fatty liver disease, and investigated whether baseline FGF21 could predict incident atherosclerotic cardiovascular disease in a 7-year prospective cohort. Methods and Results Baseline serum FGF21 was measured in a cross-sectional cohort of 371 patients with type 2 diabetes mellitus without nonalcoholic fatty liver disease (determined by hepatic magnetic resonance spectroscopy), and in a population-based prospective cohort of 705 patients from the Shanghai Diabetes Study. In the cross-sectional study, FGF21 was significantly higher in patients with than in those without subclinical carotid atherosclerosis (
<0.01). The association remained significant after adjusting for demographic and traditional cardiovascular risk factors. In the prospective cohort, 80 patients developed atherosclerotic cardiovascular disease during follow-up. Baseline FGF21 was significantly higher in those who developed ischemic heart disease or cerebral infarction than in those who did not. Using a cutoff serum concentration of 232.0 pg/mL, elevated baseline FGF21 independently predicted incident total atherosclerotic cardiovascular disease events, ischemic heart disease, and cerebral infarction in a nondiabetic population (all
<0.05), and significantly improved the discriminatory and reclassifying abilities of our prediction model after adjustment for established cardiovascular risk factors. Conclusions This study provides the first evidence that FGF21 levels are elevated in patients without nonalcoholic fatty liver disease with subclinical atherosclerosis. Baseline FGF21 is an independent predictor of atherosclerotic cardiovascular disease and represents a novel biomarker for primary prevention in the general population.
We described a challenge named “Diabetic Retinopathy (DR)—Grading and Image Quality Estimation Challenge” in conjunction with ISBI 2020 to hold three sub-challenges and develop deep learning models ...for DR image assessment and grading. The scientific community responded positively to the challenge, with 34 submissions from 574 registrations. In the challenge, we provided the DeepDRiD dataset containing 2,000 regular DR images (500 patients) and 256 ultra-widefield images (128 patients), both having DR quality and grading annotations. We discussed details of the top 3 algorithms in each sub-challenges. The weighted kappa for DR grading ranged from 0.93 to 0.82, and the accuracy for image quality evaluation ranged from 0.70 to 0.65. The results showed that image quality assessment can be used as a further target for exploration. We also have released the DeepDRiD dataset on GitHub to help develop automatic systems and improve human judgment in DR screening and diagnosis.
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•Provides the DeepDRiD dataset, performance evaluation, top methods and results•Presents deep learning approaches in DR image quality assessment and grading•Discusses the future work of DR automatic screening
Diabetic retinopathy (DR) is the most common disease caused by diabetes. Challenges are held to address real-world issues encountered in the design of DR automated screening systems to advance the technology in this area. Thus, we described a challenge named "Diabetic Retinopathy (DR)—Grading and Image Quality Estimation Challenge" in conjunction with the IEEE International Symposium on Biomedical Imaging (ISBI 2020) for fundus image assessment and DR grading. The scientific community responded positively to the challenge. In the challenge, we provided a deep DR image dataset (DeepDRiD) containing regular DR images and ultra-widefield (UWF) DR images, both having image quality and DR grading diagnosis. We discussed details of the three best algorithms in each sub-challenges. The results by the top algorithms showed that image quality assessment can be used as a target for further exploration.
In DeepDRiD challenge, organizers hold a real-world exploration in diabetic retinopathy (DR) auto-screening systems using regular fundus images from 500 participants and ultra-widefield fundus images from 128 participants. Among the 34 participating teams, we summarized the top 3 teams in the three sub-challenges involved in DR grading and image quality assessment. In addition to providing new insights into image quality assessment strategy, these models can enhance the judgment of healthcare workers in DR screening and bring precise screening results.
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