Huating Li

Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride

BACKGROUND & AIMS Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver in response to peroxisome proliferator-activated receptor-α (PPARα) activation, has recently been shown to possess beneficial effects on lipid metabolism and hepatic steatosis in animal models. This study investigated the association of FGF21 with nonalcoholic fatty liver disease (NAFLD) in Chinese patients. METHODS Serum FGF21 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 224 NAFLD and 124 control subjects, and their association with parameters of adiposity, glucose, and lipid profiles and levels of liver injury markers was studied. Besides serum concentrations, the mRNA expression of FGF21 in the liver tissue was also quantified by real-time PCR in 17 subjects with different degrees of steatosis, and was correlated with the levels of intrahepatic lipid. The protein levels of FGF21 were determined by quantitative ELISA. RESULTS Serum FGF21 levels in patients with NAFLD (402.38 pg/ml [242.03, 618.25]) were significantly higher than those in control subjects (198.62 pg/ml [134.96, 412.62]) (p<0.01). In human liver tissues, FGF21 mRNA expression increased with the degree of steatosis. Both FGF21 mRNA expression and serum FGF21 concentrations were positively correlated with intrahepatic triglyceride (TG) having r = 0.692 and r = 0.662, respectively, at p<0.01. Furthermore, the increased expression of FGF21 was accompanied by elevated protein levels in liver tissues. CONCLUSIONS These results support the role of FGF21 as a key regulator of hepatic lipid metabolism in humans, and suggest that serum FGF21 can be potentially used as a biomarker for NAFLD.

Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals.

OBJECTIVES Osteocalcin, a bone-derived protein, has recently been reported to affect energy metabolism. We investigated the relationship between serum osteocalcin and parameters of adiposity, glucose tolerance, and lipid profile in Chinese subjects. METHODS Serum osteocalcin was measured by electrochemiluminescence immunoassay in 254 men (128 with newly diagnosed type 2 diabetes mellitus (T2DM) and 126 with normal glucose tolerance (NGT)), 66 premenopausal women (33 with T2DM and 33 with NGT) as well as 180 postmenopausal women (92 with T2DM and 88 with NGT). Their associations with parameters of adiposity, glucose tolerance, and lipid profile were examined. RESULTS Serum osteocalcin concentrations in diabetic patients were significantly lower than those in NGT subjects after adjusted for age, gender, and body mass index (P=0.003). Postmenopausal women had higher osteocalcin concentrations than premenopausal women and men (both P<0.001). Multiple stepwise regression analysis showed that age, %fat, high-density lipoprotein cholesterol, fasting plasma glucose, and fasting serum insulin were independently associated with osteocalcin in men (P<0.05). Age and HbA1c were independently correlated with osteocalcin in postmenopausal women. Besides age and HbA1c, serum triglyceride was also an independent factor influencing osteocalcin in premenopausal women. In addition, osteocalcin was also positively associated with homeostasis model assessment of beta-cell function. Furthermore, multiple logistic regression analysis demonstrated that osteocalcin was independently associated with T2DM. CONCLUSIONS Serum osteocalcin was closely associated with not only fat and glucose metabolism but also with lipid metabolism.

Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice

Background 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. Objective Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. Methods ApoE−/−/TLR4mut mice and ApoE−/−/TLR4 wild-type mice (ApoE−/−/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE−/−) strain with TLR4-mutant (TLR4mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. Results 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−/−/TLR4mut 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−/−/TLR4mut 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. Conclusions 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.

Glycated haemoglobin A1c for diagnosing diabetes in Chinese population: cross sectional epidemiological survey

Objectives To evaluate haemoglobin A1c (HbA1c) in diagnosing diabetes and identify the optimal HbA1c threshold to be used in Chinese adults. Design Multistage stratified cross sectional epidemiological survey. Setting Shanghai, China, 2007-8. Participants 4886 Chinese adults over 20 years of age with no history of diabetes. Main outcome measures Performance of HbA1c at increasing thresholds for diagnosing diabetes. Results The area under the receiver operating characteristics curve for detecting undiagnosed diabetes was 0.856 (95% confidence interval 0.828 to 0.883) for HbA1c alone and 0.920 (0.900 to 0.941) for fasting plasma glucose alone. Very high specificity (96.1%, 95% confidence interval 95.5% to 96.7%) was achieved at an HbA1c threshold of 6.3% (2 SD above the normal mean). Moreover, the corresponding sensitivity was 62.8% (57.1% to 68.3%), which was equivalent to that of a fasting plasma glucose threshold of 7.0 mmol/l (57.5%, 51.7% to 63.1%) in detecting undiagnosed diabetes. In participants at high risk of diabetes, the HbA1c threshold of 6.3% showed significantly higher sensitivity (66.9%, 61.0% to 72.5%) than both fasting plasma glucose ≥7.0 mmol/l (54.4%, 48.3% to 60.4%) and HbA1c ≥6.5% (53.7%, 47.6% to 59.7%) (P<0.01). Conclusions An HbA1c threshold of 6.3% was highly specific for detecting undiagnosed diabetes in Chinese adults and had sensitivity similar to that of using a fasting plasma glucose threshold of 7.0 mmol/l. This optimal HbA1c threshold may be suitable as a diagnostic criterion for diabetes in Chinese adults when fasting plasma glucose and oral glucose tolerance tests are not available.

Serum Fibroblast Growth Factor 21 Is Associated with Adverse Lipid Profiles and γ-Glutamyltransferase But Not Insulin Sensitivity in Chinese Subjects

OBJECTIVE Fibroblast growth factor (FGF) 21, a hormone primarily secreted by liver, has recently been shown to have beneficial effects on glucose and lipid metabolism and insulin sensitivity in animal models. This study investigated the association of serum FGF21 levels with insulin secretion and sensitivity, as well as circulating parameters of lipid metabolism and hepatic enzymes in Chinese subjects. DESIGN Serum FGF21 levels were determined by ELISA in 134 normal glucose tolerance (NGT), 101 isolated-impaired fasting glucose, and 118 isolated-impaired glucose tolerance (I-IGT) Chinese subjects, and their association with parameters of adiposity, glucose, and lipid profiles, and levels of liver injury markers was studied. In a subgroup of this study, the hyperglycemic clamp technique was performed in 31 NGT, 17 isolated-impaired fasting glucose, and 15 I-IGT subjects to measure insulin secretion and sensitivity to test the associations with serum FGF21. RESULTS The serum FGF21 levels in I-IGT were significantly higher than NGT subjects [164.6 pg/ml (89.7, 261.0) vs. 111.8 pg/ml (58.0, 198.9); P < 0.05], and correlated positively with several parameters of adiposity. Multiple stepwise regression analysis showed an independent association of serum FGF21 with serum triglycerides, total cholesterol, and gamma-glutamyltransferase (all P < 0.05). However, FGF21 did not correlate with insulin secretion and sensitivity, as measured by hyperglycemic clamp and a 75-g oral glucose tolerance test. CONCLUSIONS Serum levels of FGF21 are closely related to adiposity, lipid metabolism, and biomarkers of liver injury but not insulin secretion and sensitivity in humans.

Optimal waist circumference cutoffs for abdominal obesity in Chinese

OBJECTIVE To determine the appropriate cutoffs for visceral fat area (VFA) measured by magnetic resonance imaging linking to risk of the metabolic syndrome (MetS) and the corresponding waist circumference in Chinese. METHODS AND RESULTS Totally 1,140 individuals (men 525, women 615) aged from 35 to 75 years were included. The components of the MetS were defined by International Diabetes Federation (IDF) and Chinese Diabetes Society (CDS) definition, respectively. Receive operating characteristic curve analyses were used to determine the appropriate cutoffs of VFA and corresponding waist circumference in the prediction of the MetS. The optimal VFA cutoff was near 80 cm(2) in identifying the MetS with two or more components but not including overweight/obesity by either of the two definitions in all subjects. There was no difference in men by ages while women aged < 50 years tended to have lower VFA cutoff than those aged > or = 50 years by the two definitions. The appropriate waist circumference cutoffs were 90 cm in men and 85 cm in women for the MetS. CONCLUSION The optimal cutoff of waist circumference for abdominal obesity is 90 cm for men and 85 cm for women in Chinese.

Sodium Butyrate Stimulates Expression of Fibroblast Growth Factor 21 in Liver by Inhibition of Histone Deacetylase 3

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.

Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis.

Background: Although both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1α-XBP1 pathway, FGF21 could alleviate ER stress-induced liver steatosis. Conclusion: FGF21 acts as a metabolic effector of the UPR program, exerting feedback effects upon lipid metabolism. Significance: These findings reveal a regulatory mechanism linking FGF21 actions to metabolic ER stress. Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR) and represents a critical mechanism that underlies metabolic dysfunctions. Fibroblast growth factor 21 (FGF21), a hormone that is predominantly secreted by the liver, exerts a broad range of effects upon the metabolism of carbohydrates and lipids. Although increased circulating levels of FGF21 have been documented in animal models and human subjects with obesity and nonalcoholic fatty liver disease, the functional interconnections between metabolic ER stress and FGF21 are incompletely understood. Here, we report that increased ER stress along with the simultaneous elevation of FGF21 expression were associated with the occurrence of nonalcoholic fatty liver disease both in diet-induced obese mice and human patients. Intraperitoneal administration of the ER stressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activation of the three canonical UPR branches and increased the expression of FGF21. Furthermore, the IRE1α-XBP1 pathway of the UPR could directly activate the transcriptional expression of Fgf21. Administration of recombinant FGF21 in mice alleviated tunicamycin-induced liver steatosis, in parallel with reduced eIF2α-ATF4-CHOP signaling. Taken together, these results suggest that FGF21 is an integral physiological component of the cellular UPR program, which exerts beneficial feedback effects upon lipid metabolism through counteracting ER stress.

Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice

Acetaminophen (APAP) overdose is a leading cause of drug‐induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte‐secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP‐induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose‐induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild‐type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP‐induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator‐activated receptor coactivator protein‐1α (PGC‐1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2‐related factor 2 (Nrf2) and subsequent up‐regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up‐regulation of Nrf2 and antioxidant genes and alleviation of APAP‐induced oxidative stress and liver injury were largely abolished by adenovirus‐mediated knockdown of hepatic PGC‐1α expression, whereas overexpression of PGC‐1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP‐induced hepatotoxicity. Conclusion: The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug‐induced hepatotoxicity, by enhancing PGC‐1α/Nrf2‐mediated antioxidant capacity in the liver. (Hepatology 2014;60:977–989)

Serum levels of osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in Chinese men

Objective  Osteocalcin is a bone‐derived protein and has been shown to play an important role in regulating glucose and fat metabolism. We therefore investigated the association of serum levels of osteocalcin with the metabolic syndrome (MS) and coronary atherosclerosis in Chinese men.