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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 (PZ0.003). 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 b-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.

Background: Although both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1␣-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.

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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-1a (PGC1a), 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 adenovirusmediated knockdown of hepatic PGC-1a expression, whereas overexpression of PGC-1a 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-1a/Nrf2-mediated antioxidant capacity in the liver. (HEPATOLOGY 2014;60:977-989) See Editorial on Page 792 A cetaminophen (APAP) is a commonly used over-the-counter analgesic drug with an excellent safety profile when administered in proper therapeutic doses. However, overdose of APAP can cause acute and severe liver injury. In many developed countries, APAP-induced hepatotoxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation.1 Mechanistically, APAP is metabolized by the cytochrome P450 system into its reactive intermediate N-acetyl-pAbbreviations: Aco, acyl-coenzyme A oxidase; ALI, acute liver injury; ALT, alanine transaminase; AST, aspartate aminotransferase; APAP, acetaminophen; CYP2E1, cytochrome P450 2E1; CYP4A10, cytochrome P450 4A10; FGF21, fibroblast growth factor 21; G6PDH, glucose-6-phosphate dehydrogenase; GCL-c, g-glutamylcysteine ligase catalytic subunit; Gpx-1, glutathione peroxidase-1; GSH, glutathione; JNK, c-Jun N-terminal kinase; NAC, N-acetylcysteine; NAPQI, N-acetyl-p-benzoquinone imine; Nox-2, NADPH oxidase-2; Nrf2, nuclear factor erythroid 2-r...

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.

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 HbA 1c 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 HbA 1c 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 HbA 1c 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 HbA 1c ≥6.5% (53.7%, 47.6% to 59.7%) (P<0.01). Conclusions An HbA 1c 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 HbA 1c 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.

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.