Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling.

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/ß-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

Novel insights into the pathogenic impact of diabetes on the gastrointestinal tract.

Type 2 and type 1 diabetes are common endocrine disorders with a progressively increasing incidence worldwide. These chronic, systemic diseases have multiorgan implications, and the whole gastrointestinal (GI) tract represents a frequent target in terms of symptom appearance and interdependent pathophysiological mechanisms. Metabolic alterations linked with diabetic complications, neuropathy and disrupted hormone homeostasis can lead to upper and/or lower GI symptoms in up to 75% of diabetic patients, with multifactorial involvement of the oesophagus, stomach, upper and lower intestine, and of the gallbladder. On the other hand, altered gastrointestinal motility and/or secretions are able to affect glucose and lipid homeostasis in the short and long term. Finally, diabetes has been linked with increased cancer risk at different levels of the GI tract. The presence of GI symptoms and a comprehensive assessment of GI function should be carefully considered in the management of diabetic patients to avoid further complications and to ameliorate the quality of life. Additionally, the presence of gastrointestinal dysfunction should be adequately managed to improve metabolic homeostasis, the efficacy of antidiabetic treatments and secondary prevention strategies.

Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD).

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent metabolic chronic liver diseases in developed countries and puts the populations at risk of progression to liver necro-inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction is involved in the onset of NAFLD and contributes to the progression from NAFLD to nonalcoholic steatohepatitis (NASH). Thus, liver mitochondria could become the target for treatments for improving liver function in NAFLD patients. This chapter describes the most important steps used for potential therapeutic interventions in NAFLD patients, discusses current options gathered from both experimental and clinical evidence, and presents some novel options for potentially improving mitochondrial function in NAFLD.

Multiplying effects of COVID-19 lockdown on metabolic risk and fatty liver.

BACKGROUND: Social containment measures imposed in Europe during the lockdown to face COVID-19 pandemic can generate long-term potential threats for metabolic health. METHODS: A cohort of 494 non-COVID-19 subjects living in 21 EU countries were interviewed by an anonymous questionnaire exploring anthropometric and lifestyle changes during 1-month lockdown. A subgroup of 41 overweight/obese Italian subjects with previously diagnosed nonalcoholic fatty liver (NAFLD) joined the study following a 12-month follow-up period promoting weight loss by healthy lifestyle. RESULTS: During the lockdown, body weight increased in 55% of subjects (average 2.4 ± 0.9 kg). Weight change increased with age, but not baseline body mass index. Subjects living in Italy had greater weight gain than those living in other European Countries. Weight gain during the lockdown was highest in subjects reporting no physical activity, and low adherence to Mediterranean diet. In the NAFLD group, weight gain occurred in 70% of cases. Subjects reporting weight loss during lockdown had decreased fatty liver score at 3 months before the lockdown, as compared with 1 year before. CONCLUSIONS: Strict measures of social containment-even short-term-pave the way to the increased risk of metabolic abnormalities in the medium-long term. In this context, adherence to Mediterranean diet and regular physical activity play a protective role both in terms of weight gain and fatty liver development/progression, with implication for primary and secondary prevention. When adopting measures imposing social containment, intensive educational campaigns must increase public awareness about beneficial effects of healthy lifestyles.

Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment.

Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.

Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.

Preoperative and Intraoperative Methods of Parathyroid Gland Localization and the Diagnosis of Parathyroid Adenomas.

Accurate pre-operative determination of parathyroid glands localization is critical in the selection of minimally invasive parathyroidectomy as a surgical treatment approach in patients with primary hyperparathyroidism (PHPT). Its importance cannot be overemphasized as it helps to minimize the harmful side effects associated with damage to the parathyroid glands such as in hypocalcemia, severe hemorrhage or recurrent laryngeal nerve dysfunction. Preoperative and intraoperative methods decrease the incidence of mistakenly injuring the parathyroid glands and allow for the timely diagnosis of various abnormalities, including parathyroid adenomas. This article reviews 139 studies conducted between 1970 and 2020 (49 years). Studies that were reviewed focused on several techniques including application of carbon nanoparticles, carbon nanoparticles with technetium sestamibi (99m Tc-MIBI), Raman spectroscopy, near-infrared autofluorescence, dynamic optical contrast imaging, laser speckle contrast imaging, shear wave elastography, and indocyanine green to test their potential in providing proper parathyroid glands' localization. Apart from reviewing the aforementioned techniques, this study focused on the applications that helped in the detection of parathyroid adenomas. Results suggest that applying all the reviewed techniques significantly improves the possibility of providing proper localization of parathyroid glands, and the application of indocyanine green has proven to be the 'ideal' approach for the diagnosis of parathyroid adenomas.

Exercise and apulian hypocaloric diet affect adipokine changes and gastric banding-induced weight loss: A prospective study on severe obese subjects.

BACKGROUND: Adiponectin and Resistin correlate with insulin sensitivity and cardiovascular risk, respectively. This study aimed to identify lifestyle factors that modulate changes in Adiponectin and Resistin levels after gastric banding positioning (LapGB). MATERIALS AND METHODS: Before (T0), 3 months (T3), 6 months (T6), and 12 months (T12) after LapGB, serum Adiponectin and Resistin levels were evaluated in a single-centre prospective study including a cohort of 27 non-diabetic obese subjects (S-Ob, BMI ≥35 kg/m2). After surgery, a dietitian checked the adherence of S-Ob to an Apulian hypocaloric diet (aphypoD)/physical activity (phA) and, according to their high or low compliance to aphypoD/phA, S-Ob were included in group 1 (n = 14) or 2 (n = 13) respectively. Serum Adiponectin and Resistin were also measured in 10 healthy controls. RESULTS: At baseline, Resistin levels were significantly higher and Adiponectin levels significantly lower in S-Ob than in controls. After surgery, group 1 showed a 50.2% excess weight loss (%EWL), significantly decreased Resistin levels at T12 and increased Adiponectin levels at both T6 and T12 as compared with baseline. Group 2 showed 24.6 %EWL at T12, decreased Adiponectin levels at T6 and T12 as compared with baseline, but unaltered Resistin levels. After surgery, group 1 followed aphypoD/phA, while group 2 did not. CONCLUSIONS: LapGB fails to improve cardiovascular risk markers (Resistin) in S-Ob not improving lifestyle. Future studies might investigate these findings in a larger cohort and display whether aphypoD is more effective than other dietary intervention on cardiovascular risk in subjects undergoing LapGB or other Bariatric procedures.

Weighing the Impact of Diet and Lifestyle on Female Reproductive Function.

BACKGROUND: In the last years, several scientific societies and expert groups focused on the role played by nutritional factors, lifestyle and excess of body fat in interfering with female reproduction and fertility. In many studies a confounding factor is represented by polycystic ovary syndrome (PCOS) which is one of the major causes of infertility where genetic and family history are certainly playing a role, together with lifestyle and nutritional factors. METHODS: In an attempt to define "the optimal fertility diet", we consider the role played by Mediterranean lifestyle and some macronutrients (animal and vegetable proteins) on ovulatory disorders and female fertility also considering some new visions derived from randomized trials of lifestyle programs in obese infertile women asking for in vitro fertilization or alternative assisted reproduction technologies. RESULTS: Several reports are in favor of an increased consumption of either proteins or low-glycemic index carbohydrates to improve ovulatory disorders and female fertility. In studies concerning infertile women undergoing assisted reproduction, either structured exercise sessions and dietary intervention programs seem to be effective in improving menstrual cycles and fertility as demonstrated by the increased rate of natural conceptions. CONCLUSION: The findings of this review confirm the important impact of Mediterranean diet and lifestyle in preserving and improving fertility. However, epigenetic factors are very important in determining fertility rate, but genetic background and ethnicity are also playing crucial roles.

The Food-gut Human Axis: The Effects of Diet on Gut Microbiota and Metabolome.

Gut microbiota, the largest symbiont community hosted in human organism, is emerging as a pivotal player in the relationship between dietary habits and health. Oral and, especially, intestinal microbes metabolize dietary components, affecting human health by producing harmful or beneficial metabolites, which are involved in the incidence and progression of several intestinal related and non-related diseases. Habitual diet (Western, Agrarian and Mediterranean omnivore diets, vegetarian, vegan and gluten-free diets) drives the composition of the gut microbiota and metabolome. Within the dietary components, polymers (mainly fibers, proteins, fat and polyphenols) that are not hydrolyzed by human enzymes seem to be the main leads of the metabolic pathways of gut microbiota, which in turn directly influence the human metabolome. Specific relationships between diet and microbes, microbes and metabolites, microbes and immune functions and microbes and/or their metabolites and some human diseases are being established. Dietary treatments with fibers are the most effective to benefit the metabolome profile, by improving the synthesis of short chain fatty acids and decreasing the level of molecules, such as p-cresyl sulfate, indoxyl sulfate and trimethylamine N-oxide, involved in disease state. Based on the axis diet-microbiota-health, this review aims at describing the most recent knowledge oriented towards a profitable use of diet to provide benefits to human health, both directly and indirectly, through the activity of gut microbiota.

Cross-Talk Between Bile Acids and Gastro-Intestinal and Thermogenic Hormones: Clues from Bariatric Surgery

Obesity is rapidly increasing and has reached epidemic features worldwide. It´s linked to insulin resistance, systemic low-grade inflammation and common pathogenic pathways with a number of comorbidities (including cancer), leading to high mortality rates. Besides change of lifestyles (diet and physical exercise) and pharmacological therapy, bariatric surgery is able to rapidly improve several metabolic and morphologic features associated with excessive fat storage, and currently represents an in vivo model to study the pathogenic mechanisms underlying obesity and obesity-related complications. Studies on obese subjects undergoing bariatric surgery find that the effects of surgery are not simply secondary to gastric mechanical restriction and malabsorption which induce body weight loss. In fact, some surgical procedures positively modify key pathways involving the intestine, bile acids, receptor signaling, gut microbiota, hormones and thermogenesis, leading to systemic metabolic changes. Furthermore, bariatric surgery represents a suitable model to evaluate the gene-environment interaction and some epigenetic mechanisms linking obesity and insulin resistance to metabolic diseases.

The dangerous link between childhood and adulthood predictors of obesity and metabolic syndrome.

The purpose of this review is to evaluate whether some risk factors in childhood work as significant predictors of the development of obesity and the metabolic syndrome in adulthood. These factors include exposures to risk factors in the prenatal period, infancy and early childhood, as well as other socio-demographic variables. We searched articles of interest in PubMed using the following terms: 'predictors AND obesity OR Metabolic syndrome AND (children OR adolescents) AND (dyslipidemia OR type 2 diabetes OR atherosclerosis OR hypertension OR hypercholesterolemia OR cardiovascular disease)' AND genetic OR epigenetic. Maternal age, smoking and weight gain during pregnancy, parental body mass index, birth weight, childhood growth patterns (early rapid growth and early adiposity rebound), childhood obesity and the parents' employment have a role in early life. Furthermore, urbanization, unhealthy diets, increasingly sedentary lifestyles and genetic/epigenetic variants play a role in the persistence of obesity in adulthood. Health promotion programs/agencies should consider these factors as reasonable targets to reduce the risk of adult obesity. Moreover, it should be a clinical priority to correctly identify obese children who are already affected by metabolic comorbidities.

Obesity and the risk and prognosis of gallstone disease and pancreatitis.

Obesity is a risk factor for the formation of cholesterol gallstones and exposes patients to increased risk of gallstone-related complications and cholecystectomy. Rapid weight loss achieved by very low calorie diets or bariatric surgery is also a risk factor for cholelithiasis in obese patients, and therapy should take into account the higher prevalence of gallstones, the possibility of more frequent complications and the need for prophylactic treatment with oral ursodeoxycholic acid during weight loss. Obesity is also frequent in children and adolescents, and the burden of cholesterol cholelithiasis is increasing in this population. The chance to develop acute pancreatitis and the severity of the disease are higher in obese subjects because of specific pathogenic factors, including supersaturated bile and crystal formation, rapid weight loss, and visceral obesity. All health policies aimed at reducing the incidence of obesity worldwide will decrease the incidence of gallstones and gallstone-related complications. The pathophysiological scenarios and the therapeutic implications for obesity, gallstone disease, and pancreatitis are discussed.

Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol.

BACKGROUND: Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors and represents a failure of biliary cholesterol homoeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. DESIGN: The primary pathophysiologic event is persistent hepatic hypersecretion of biliary cholesterol, which has both hepatic and small intestinal components. The majority of the environmental factors are probably related to Western-type dietary habits, including excess cholesterol consumption. RESULTS: Laparoscopic cholecystectomy, one of the most commonly performed surgical procedures in the United States, is nowadays a major treatment for gallstones. However, it is invasive and can cause surgical complications, and not all patients with symptomatic gallstones are candidates for surgery. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been employed as first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol gallstones. Long-term administration of UDCA can promote the dissolution of cholesterol gallstones. However, the optimal use of UDCA is not always achieved in clinical practice because of failure to titrate the dose adequately. CONCLUSIONS: Therefore, the development of novel, effective and noninvasive therapies is crucial for reducing the costs of health care associated with gallstones. In this review, we summarize recent progress in investigating the inhibitory effects of ezetimibe and statins on intestinal absorption and hepatic biosynthesis of cholesterol, respectively, for the treatment of gallstones, as well as in elucidating their molecular mechanisms by which combination therapy could prevent this very common liver disease worldwide.

GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET).

Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in "in Vitro" Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH) agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.

Adipose tissue, metabolic syndrome and polycystic ovary syndrome: from pathophysiology to treatment.

In the last few years, polycystic ovary syndrome (PCOS) has deserved major attention because it is linked to the same cluster of events that promote the metabolic syndrome. This review will point out the relationships between fat excess, insulin resistance and the metabolic syndrome. Adipocytes are actually considered as endocrine cells that synthesize and release molecules (adipokines) that play an endocrine/paracrine role, such as adiponectin, atrial natriuretic peptide, leptin, resistin, tumour necrosis factor alpha (TNFalpha). Metabolic syndrome is a chronic low-grade inflammatory condition in which adipokines play a major role. Isolated adipocytes from women with PCOS express higher mRNA concentrations of some adipokines involved in cardiovascular risk and insulin resistance. However, environmental factors and lifestyle play a major role in determining the appearance of the phenotypes of PCOS. In morbid obese women with PCOS, bariatric surgery decreases bodyweight and fat excess and reverses hyperandrogenism and sterility. In lean or overweight women with PCOS, changes in lifestyle in combination with drugs reducing visceral fat and insulin resistance reverse the symptoms and signs of PCOS. Promising treatments for PCOS seem to be insulin sensitizers such as metformin and glitazones.

Expression and secretion of the atrial natriuretic peptide in human adipose tissue and preadipocytes.

OBJECTIVE: Atrial natriuretic peptide (ANP) is a secretory hormone displaying diuretic, natriuretic, and vasorelaxant activities. Recently, its lipolytic activity has been reported. Since the expression of ANP in adipose tissue has not been documented, we used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to investigate the expression of ANP in human adipose tissue and preadipocytes. RESEARCH METHODS AND PROCEDURES: RNA was extracted from the human adipose tissue of severely obese premenopausal women as well as from human preadipocytes. For human preadipocytes, two cell systems were investigated: the human preadipose immortalized (Chub-S7) cells, a well-characterized human preadipose cell line, and primary preadipocytes derived from the stromal vascular fraction of the human adipose tissue. We measured the mRNA of ANP, of corin (a transmembrane serine protease involved in the conversion of pro-ANP to ANP) and of uncoupling protein 2 (UCP2; a control gene known to be ubiquitously expressed). The expression of ANP was also investigated using immunofluorescence and radioimmunoassay in Chub-S7 cells and human primary preadipocytes in culture. RESULTS: Our results indicate that ANP and corin are expressed at the mRNA level in human adipose tissue and preadipocytes. Immunofluorescence experiments demonstrated that pro-ANP was expressed in Chub-S7 cells. In addition, ANP secretion could be measured in Chub-S7 cells and human primary preadipocytes in culture. Rosiglitazone, a selective peroxisome proliferator-activated receptor type gamma (PPAR-gamma) agonist promoting adipocyte differentiation, was found to modulate both ANP expression and secretion in preadipocytes. DISCUSSION: Our findings suggest the existence of an autocrine/paracrine system for ANP in the human adipose tissue whose implications in lipolysis and cardiovascular function need to be further explored.