The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans.

Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined

Telomere length elongation after weight loss intervention in obese adults

INTRODUCTION: Telomeres may be considered markers of biological aging, shorter telomere length is associated with some age-related diseases; in several studies short telomere length has also been associated to obesity in adults and adolescents. However the relationship between telomere complex functions and obesity is still not clear. Aim of the study was to assess telomere length (TL) in adults' obese subjects before and after weight loss obtained by placement of bioenteric intragastric balloon (BIB) for 6months. METHODS: We enrolled 42 obese subjects before and after BIB placement as weight loss intervention. Blood samples were collected in order to obtain DNA from leukocyte to measure TL by quantitative PCR. RESULTS: Data were analyzed only in 37 subjects with complete data; all presented important body weight loss (124.06\ub126.7 vs 105.40\ub123.14, p<0.001) and more interesting they presented a significant increase in TL (3.58\ub10.83 vs 5.61\ub13.29, p<0.001). Moreover we observed a significant positive correlation between TL elongation and weight loss (r=0.44, p=0.007) as well as an inverse correlation between TL at baseline and TL elongation (r=-0.35, p=0.03).The predictors of TL elongation were once again weight loss and short TL at baseline (respectively p=0.007 and p=0.003). CONCLUSIONS: Our study shows that weight loss is associated to telomere lengthening in a positive correlation: the greater weight loss the greater telomere lengthening; moreover telomere lengthening is more significant in those subjects with shortest telomeres at baseline.Introduction: Telomeres may be considered markers of biological aging, shorter telomere length is associated with some age-related diseases; in several studies short telomere length has also been associated to obesity in adults and adolescents. However the relationship between telomere complex functions and obesity is still not clear. Aim of the study was to assess telomere length (TL) in adults' obese subjects before and after weight loss obtained by placement of bioenteric intragastric balloon (BIB) for 6 months. Methods: We enrolled 42 obese subjects before and after BIB placement as weight loss intervention. Blood samples were collected in order to obtain DNA from leukocyte to measure TL by quantitative PCR. Results: Data were analyzed only in 37 subjects with complete data; all presented important body weight loss (124.06 \ub1 26.7 vs 105.40 \ub1 23.14, p < 0.001) and more interesting they presented a significant increase in TL (3.58 \ub1 0.83 vs 5.61 \ub1 3.29, p < 0.001). Moreover we observed a significant positive correlation between TL elongation and weight loss (r = 0.44, p = 0.007) as well as an inverse correlation between TL at baseline and TL elongation (r = - 0.35, p = 0.03).The predictors of TL elongation were once again weight loss and short TL at baseline (respectively p = 0.007 and p = 0.003). Conclusions: Our study shows that weight loss is associated to telomere lengthening in a positive correlation: the greater weight loss the greater telomere lengthening; moreover telomere lengthening is more significant in those subjects with shortest telomeres at baseline

Nonalcoholic fatty liver disease and aging: epidemiology to management

Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients

Do Nonalcoholic Fatty Liver Disease and Fetuin-A Play Different Roles in Symptomatic Coronary Artery Disease and Peripheral Arterial Disease?

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with both atherosclerotic cardiovascular disease (CVD) and Fetuin-A. However, the association of Fetuin-A with atherosclerosis is more controversial. We hypothesized that the pathogenic interplay of NAFLD, Fetuin-A and atherosclerosis varies based on arterial site. Accordingly, we aimed to assess NAFLD prevalence, Fetuin-A values and their relationship with symptomatic atherosclerosis occurring in different localizations: coronary artery disease (CAD) vs. peripheral arterial disease (PAD)

Relationship of Serum Fetuin-A Levels with Coronary Atherosclerotic Burden and NAFLD in Patients Undergoing Elective Coronary Angiography

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Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.

BACKGROUND: The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols. METHODS: We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids). RESULTS: A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age. CONCLUSION: These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined

Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients

Introduction: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects.Methods: Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.Results: 365 patients were enrolled, and 289 patients with follow-up (age 67.7 &amp; PLUSMN; 7.3 years, 237 males, mean follow-up 40 &amp; PLUSMN; 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project.Conclusions: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered

Glia-derived steroids modulate epileptogenesis in a model of temporal lobe epilepsy

Purpose: The conversion of cholesterol into pregnenolone by cytochromeP450 cholesterol side-chain cleavage enzyme (P450 scc) is therate-limiting step in the steroid synthesis. Glial cells and neurons bothexpress P450 scc and synthesize neurosteroids, which are positive modulatorsof GABAergic transmission. Astrocytes become activated followingstatus epilepticus (SE), but it is presently unclear whether thisactivation leads to enhanced neurosteroidogenesis.Method: We studied the time course of P450 scc immunoreactivitychanges after pilocarpine-induced SE in adult (8 week-old) and young (3weeks-old) rats. To evaluate the role of P450 scc upregulation, we usedthe 5a-reductase inhibitor finasteride (100/kg s.c. for 3 weeks) to suppressthe synthesis of neurosteroids.Results: We demonstrated that P450 scc is upregulated in the CA3 hippocampalregion. Moreover the extent of P450 scc induction was directlyrelated to the onset of spontaneous recurrent seizures in adult (8-weekold)rats. In 3-week-old rats compared with adults, higher P450 scc levelsand a longer latent period were found. Interestingly, adult epileptic rats,treated with finasteride, compared with a group of vehicle-treated rats,presented anticipated generalized seizures (p<0.01). In young rats, finasterideanticipates seizures in approximately 50% of the animals.Conclusion: These findings suggest that neurosteroids can modulateepileptogenesis in the pilocarpine model of temporal lobe epilepsy

Glia-derived neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy

The conversion of cholesterol intopregnenolone by the enzyme cholesterolside-chain cleavage cytochromeP450 (P450scc) is the rate-limitingstep in the steroid synthesis. Glialcells and neurons both expressP450scc and synthesize neurosteroidsthat act as positive modulators ofGABAergic transmission. Astrocytesbecome activated following statusepilepticus (SE), but it is presently unclearwhether this activation leads toenhanced neurosteroid synthesis. Westudied the time course of P450sccimmunoreactivity changes afterpilocarpine-induced SE and its relationshipwith epileptogenesis. Wefound that P450scc is upregulated inthe CA3 hippocampal region, afterSE. Induction of P450scc was mainlyobserved in astrocytes identified by aGFAP antibody, although hemeoxygenase-1-positive microglial cells,RIP-positive oligodendrocytes andNeuN-neurons were also stained forP450scc (Fig. 1). The extent ofP450scc induction was directly relatedwith the onset of spontaneouslyrecurrent seizures in adult (8-weekold)rats. In addition, in young (3-week-old) rats the induction ofP450scc and the latent period durationwere much larger than in adultrats. To further evaluate the role ofP450scc upregulation, we used the5-reductase inhibitor finasteride(100 mg/kg/day for approximately 3weeks) to suppress the synthesis ofGABA-modulating neurosteroidssuch as allopregnanolone. Interestingly,adult epileptic rats, comparedwith a group of vehicle-treated ratsthat experienced a similar SE, presentedwith significantly (p<0.01) anticipatedgeneralized seizures whentreated with finasteride. In young rats,we observed early generalized seizuresin approximately 50% of the animals.These findings suggest thatneurosteroids can modulate epileptogenesisin the pilocarpine modelof temporal lobe epilepsy