Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation.

The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical-chemical state of bile predisposing to supersaturation with cholesterol.

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.

Genetic Analysis of Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis.

Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC.

Impact of Sequential Lipid Meals on Lymphatic Lipid Absorption and Transport in Rats.

The sequential meal pattern has recently received more attention because it reflects a phycological diet style for human beings. The present study investigated the effects of the second lipid meal on lymphatic lipid absorption and transport in adult rats following a previous lipid meal. Using the well-established lymph fistula model, we found that the second lipid meal significantly increased the lymphatic output of triglycerides, cholesterol, phospholipids, and non-esterified fatty acids compared with a single lipid meal.

Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis.

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions.

Intestinal Barrier and Permeability in Health, Obesity and NAFLD.

The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors.

Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids.

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice.

Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests.

The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells.

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.

Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e.

Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.

Objective: Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice and patients with non-alcoholic steatohepatitis (NASH), yet hepatocyte miR-34a's role in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.

Methods: Mice overexpressing or deficient in hepatocyte miR-34a and control mice were fed a diet enriched in fats, cholesterol, and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo.

Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.

Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr or Apoe mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone.

Emerging Trends in Deciphering the Pathogenesis of Human Diseases through Genetic Analysis.

Any changes in gene expression or protein functions can cause abnormal anatomical, physiological, biochemical, and behavioral modifications in human beings, which can lead to disease [...

Regulation of Cholesterol Metabolism by Bioactive Components of Soy Proteins: Novel Translational Evidence.

Hypercholesterolemia represents one key pathophysiological factor predisposing to increasing risk of developing cardiovascular disease worldwide. Controlling plasma cholesterol levels and other metabolic risk factors is of paramount importance to prevent the overall burden of disease emerging from cardiovascular-disease-related morbidity and mortality. Dietary cholesterol undergoes micellization and absorption in the small intestine, transport via blood, and uptake in the liver.

Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 mouse model of PFIC3.

Background & Aims: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation.

Methods: We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (hABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs).

Estradiol Enhances Anorectic Effect of Apolipoprotein A-IV through ERα-PI3K Pathway in the Nucleus Tractus Solitarius.

Estradiol (E2) enhances the anorectic action of apolipoprotein A-IV (apoA-IV), however, the intracellular mechanisms are largely unclear. Here we reported that the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway was significantly activated by E2 and apoA-IV, respectively, in primary neuronal cells isolated from rat embryonic brainstem. Importantly, the combination of E2 and apoA-IV at their subthreshold doses synergistically activated the PI3K/Akt signaling pathway.

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases.

There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1).

Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome.

Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues.

An Update on the Lithogenic Mechanisms of Cholecystokinin a Receptor (CCKAR), an Important Gallstone Gene for .

The cholecystokinin A receptor (CCKAR) is expressed predominantly in the gallbladder and small intestine in the digestive system, where it is responsible for CCK's regulation of gallbladder and small intestinal motility. The effect of CCKAR on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. The gene has been identified to be an important gallstone gene, , in inbred mice by a powerful quantitative trait locus analysis.

Differential Effect of Four-Week Feeding of Different Dietary Fats on the Accumulation of Fat and the Cholesterol and Triglyceride Contents in the Different Fat Depots.

The aim of the present study was to determine the effects of feeding of a high-fat diet containing different types of lipids for four weeks on the cholesterol and triglyceride contents of different fat depots and on body temperature in rats. Four groups of adult rats were fed 10% fat, containing either beef tallow, safflower oil, or fish oil, respectively, as well as a normal rodent diet with 4% fat, for four weeks. The rats on normal rodent diet consumed significantly more food and water than the rats in the other three groups.

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.

Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5/G8 in Health and Disease.

Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity and mortality worldwide. Cholesterol gallstone disease is caused by complex genetic and environmental factors and is one of the most prevalent and costly digestive diseases in the USA and Europe. Although sitosterolemia is a rare inherited lipid storage disease, its genetic studies led to identification of the sterol efflux transporters ABCG5/G8 that are located on chromosome 2p21 in humans and chromosome 17 in mice.