Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

The aim of the study was to assess serum fibroblast growth factor 21 (FGF21) concentrations in Chinese type 2 diabetic patients with and without retinopathy and to assess the association between FGF21 and the severity of retinopathy. 117 diabetic patients were compared with 68 healthy controls. Fasting blood glucose, serum total cholesterol, serum triglycerides, serum insulin, and serum FGF21 levels were estimated. FGF21 concentrations in the patients were significantly higher than those in control. In the patient group there was a significant positive correlation between FGF21, insulin level, and homeostasis model assessment index. Serum FGF21 concentrations in patients with proliferative diabetic retinopathy or nonproliferative diabetic retinopathy were significantly higher than those in patients without diabetic retinopathy. When the presence of diabetes was defined as the final variable in the conditional logistic regression model with the FGF21 concentration as the continuous variable, FGF21 was significantly involved in the model. This study shows that the increase in serum concentration of FGF21 was associated with the severity of diabetic retinopathy and suggests that FGF21 may play a role in the pathogenesis of diabetic retinopathy and its degree.

Bile acids are required for intestinal absorption and biliary solubilization of cholesterol and lipids. In addition, bile acids play a crucial role in cholesterol homeostasis. One of the key enzymes in the bile acid biosynthetic pathways is cholesterol 7␣-hydroxylase/cytochrome P450 7␣-hydroxylase (7␣-hydroxylase), which is the rate-limiting and regulatory step of the "classic" pathway. Transcription of the 7␣-hydroxylase gene is highly regulated. Two nuclear receptors, hepatocyte nuclear factor 4␣ (HNF-4␣) and ␣ 1 -fetoprotein transcription factor, are required for both transcription and regulation by different physiological events. It has been shown that some mitogen-activated protein kinases, such as the c-Jun N-terminal kinase and the ERK, play important roles in the regulation of 7␣-hydroxylase transcription. In this study, we show evidence that the p38 kinase pathway plays an important role in 7␣-hydroxylase expression and hence in bile acid synthesis. Inhibition of p38 kinase activity in primary hepatocytes results in ϳ5-10-fold reduction of 7␣-hydroxylase mRNA. This suppression is mediated, at least in part, through HNF-4␣. Inhibition of p38 kinase activity diminishes HNF-4␣ nuclear protein levels and its phosphorylation in vivo and in vitro, and it renders a less stable protein. Induction of the p38 kinase pathway by insulin results in an increase in HNF-4␣ protein and a concomitant induction of 7␣-hydroxylase expression that is blocked by inhibiting the p38 pathway. These studies show a functional link between the p38 signaling pathway, HNF-4␣, and bile acid synthesis.

α1-Fetoprotein transcription factor (FTF), also known as liver receptor homolog 1 (LRH-1) is highly expressed in liver and intestine, where it is implicated in the regulation of cholesterol, bile acid and steroid hormone homeostasis. FTF is an important regulator of bile acid metabolism. We show here that FTF plays a key regulatory role in lipid homeostasis including triglyceride and cholesterol homeostasis. FTF deficient mice developed lower levels of serum triglyceride and cholesterol as a result of lower expression of several hepatic FTF target genes. Chenodeoxycholic acid repressed FTF expression resulting in a decrease in serum triglyceride in wild-type mice. The absence of chenodeoxycholic acid-mediated repression in FTF+/− mice demonstrated the essential role of FTF in triglyceride metabolism. Taken together, our results identify the nuclear receptor FTF as a central regulator of lipid metabolism.