Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.     

Identification of S-acyl glutathione conjugates of bile acids in human bile by means of LC/ESI-MS

Previous work from this laboratory has reported the biotransformation of bile acids (BA) into the thioester-linked glutathione (GSH) conjugates via the intermediary metabolites formed by BA:CoA ligase and shown that such GSH conjugates are excreted into the bile in healthy rats as well as rats dosed with lithocholic acid or ursodeoxycholic acid. To examine whether such novel BA-GSH conjugates are present in human bile, we determined the concentration of the GSH conjugates of the five BA that predominate in human bile. Bile was obtained from three infants (age 4, 10, and 13 months) and the BA-GSH conjugates quantified by means of liquid chromatography (LC)/electrospray ionization (ESI)-linear ion trap mass spectrometry (MS) in negative-ion scan mode, monitoring characteristic transitions of the analytes. By LC/ESI-MS, only primary BA were present in biliary BA, indicating that the dehydroxylating flora had not yet developed. GSH conjugates of chenodeoxycholic and lithocholic acid were present in concentrations ranging from 27 to 1120 pmol/ml, several orders of magnitude less than those of natural BA N-acylamidates. GSH conjugates were not present, however, in the ductal bile obtained from 10 adults (nine choledocholithiasis, one bile duct cancer). Our results indicate that BA-GSH conjugates are formed and excreted in human bile, at least in infants, although this novel mode of conjugation is a very minor pathway.     

Cortical regions activated after rapid eye movements during REM sleep

The present study investigated the cortical regions activated during rapid eye movement (REM) sleep by identifying the sources of electric currents of brain potentials related to rapid eye movements using low-resolution brain electromagnetic tomography (LORETA). The brain potentials measured were the lambda response (P1 and P2) during wakefulness and the lambda-like response (P1r and P2r) during REM sleep. Fifteen healthy university students participated in this study. During wakefulness, the sources of the electric current of the lambda response (P1 and P2) were estimated to be in the primary and secondary visual cortices (BA 17, 18). During REM sleep, the P1r has a source in a higher order visual area (precuneus; BA 7, 31) and P2r comes from the primary and secondary visual cortices (BA 17, 18). In addition, the density of electric current in the premotor and fronto-central regions including anterior cingulate gyrus was higher after rapid eye movements, which was a discriminative feature of REM sleep. The results of this study suggest that these activities that occur after rapid eye movements might underlie the generation of vivid visual images of dreaming.

     

Identification of Event-Related Potentials Elicited by Conceptual Mismatch Between Expectations and Self-chosen TV Images

When a voluntary action is followed by an unexpected stimulus, a late positive potential (LPP) with a posterior scalp distribution is elicited in a latency range of 500–700 ms. In the present study, we examined what type of mismatch between expectations and action outcomes was reflected by the LPP. Twelve student volunteers participated in a task simulating choice of TV programs. After choosing one of three options displayed as a cue stimulus, they viewed a second stimulus (still TV image). To manipulate the type of expectation, three kinds of cue conditions were used: thumbnail image condition (three small TV images), category label condition (three words), and no cue condition (three question marks). Over trials, the second stimulus either matched (p = .80) or mismatched (p = .20) the chosen option. As compared to matched TV images, mismatched TV images elicited a larger LPP (500–700 ms) in the thumbnail image and category label conditions. In addition, a larger centroparietal P3 (400–450 ms) was elicited to mismatched TV images in the thumbnail image condition alone. LPP reflects a conceptual mismatch between a category-based expectation and an ensuing action outcome, whereas P3 reflects a perceptual mismatch between an image-based expectation and an action outcome.     

The Power of Kawaii: Viewing Cute Images Promotes a Careful Behavior and Narrows Attentional Focus

Kawaii (a Japanese word meaning “cute”) things are popular because they produce positive feelings. However, their effect on behavior remains unclear. In this study, three experiments were conducted to examine the effects of viewing cute images on subsequent task performance. In the first experiment, university students performed a fine motor dexterity task before and after viewing images of baby or adult animals. Performance indexed by the number of successful trials increased after viewing cute images (puppies and kittens; M ± SE = 43.9±10.3% improvement) more than after viewing images that were less cute (dogs and cats; 11.9±5.5% improvement). In the second experiment, this finding was replicated by using a non-motor visual search task. Performance improved more after viewing cute images (15.7±2.2% improvement) than after viewing less cute images (1.4±2.1% improvement). Viewing images of pleasant foods was ineffective in improving performance (1.2±2.1%). In the third experiment, participants performed a global–local letter task after viewing images of baby animals, adult animals, and neutral objects. In general, global features were processed faster than local features. However, this global precedence effect was reduced after viewing cute images. Results show that participants performed tasks requiring focused attention more carefully after viewing cute images. This is interpreted as the result of a narrowed attentional focus induced by the cuteness-triggered positive emotion that is associated with approach motivation and the tendency toward systematic processing. For future applications, cute objects may be used as an emotion elicitor to induce careful behavioral tendencies in specific situations, such as driving and office work.     

Auditory event-related potentials from a single-stimulus paradigm during rapid eye movement sleep

Sleep and Biological Rhythms - Auditory evoked potentials to a 2000-Hz pure tone were recorded in wakefulness and in rapid eye movement (REM) sleep. A late positive wave with a maximal amplitude...     

A simple and accurate HPLC method for fecal bile acid profile in healthy and cirrhotic subjects: validation by GC-MS and LC-MS

We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: 1) lyophilization of the stool sample; 2) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; 3) incubation with 0.1 N NaOH in 50% isopropanol at 60°C to hydrolyze esterified bile acids; 4) extraction of bile acids from particulate material using 0.1 N NaOH; 5) isolation of deconjugated bile acids by solid phase extraction; 6) formation of phenacyl esters by derivatization using phenacyl bromide; and 7) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis.     

Serum concentrations of glucuronidated and sulfated bile acids in children with cholestasis

Serum concentrations of nonglucuronidated-nonsulfated, glucuronidated, and sulfated bile acids in 9 control children and 16 children with cholestasis were quantitated by mass fragmentography. Total bile acid levels in control children were 19.55 +/- 2.78 mumol/liter (mean +/- SEM), and glucuronidated and sulfated bile acids comprised 2.6 +/- 0.5 and 17 +/- 3.1%, respectively. In 9 patients with congenital biliary atrasia, total bile acid levels were 167.34 +/- 11.18 mumole/liter of which 2.1 +/- 0.3% were glucuronidated and 15 +/- 1.4% were sulfated. Lithocholic and 3 beta-hydroxy-5-cholenoic acids, which have hepatotoxic effects, were presented in only small amounts in cholestatic children, and they were almost all glucuronidated or sulfated. The percentages of glucuronidated bile acids in control and cholestatic children were lower than in healthy and cholestatic adults, which may be explained by the lower activity of UDP-glucuronyltransferase in neonatal liver.     

Gamma band EEG activity is enhanced after the occurrence of rapid eye movement during human REM sleep

Sleep and Biological Rhythms - This study investigated changes in gamma band (35–44 Hz) EEG activity associated with rapid eye movement (REM) during human REM sleep. Polysomnograms of eight...     

The Role of Intention to Conceal in the P300-based Concealed Information Test

The present study examined whether intention to conceal knowledge affects P300 amplitude and detection accuracy in the concealed information test. Eighteen university students were told to choose one card from five and to hide it. In the conceal condition, participants made an effort to leave their chosen card undetected by suppressing their brain response to it. In the transmit condition, they attempted to inform the experimenter of the chosen card by enhancing brain response to it. In the no secret condition, participants showed the chosen card to the experimenter beforehand and lost their motivation to conceal it. The difference in P300 amplitude between the chosen and unchosen cards was significant only in the conceal and transmit conditions. The results suggest that a larger P300 amplitude for the chosen card was not due to a deception-specific process but rather to increased significance of the item caused by additional processing.