Scientific Publications

“Mitochondria in non-alcoholic fatty liver disease”

Inês C.M. Simões, Adriana Fontes, Paolo Pinton, Hans Zischka and Mariusz R. Wieckowski

ABSTRACT 

NAFLD is a common disease in Western society and ranges from steatosis to steatohepatitis and to end-stage liver disease. The molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood. One suggested mechanism involves the oxidation of biomolecules by mitochondrial ROS which initiates a vicious cycle of exacerbated mitochondrial dysfunction and increased hepatocellular oxidative damage. This may ultimately pave the way for hepatic inflammation and liver failure. This review updates our current understanding of mitochondria-derived oxidative stress in the progression of NAFLD.

Keywords: Mitochondria, steatosis, ROS, NAFLD, NASH

November, Vol. 16 (Suppl. 1), 2017: s87-s105

"Bile Acids and Cancer: Direct and Environmental-Dependent Effects"

Agostino Di Ciaula, David Q.-H. Wang, Emilio Molina-Molina, Raquel Lunardi Baccetto, Giuseppe Calamita, Vincenzo O. Palmieri, Piero Portincasa

ABSTRACT 

Bile acids (BAs) regulate the absorption of fat-soluble vitamins, cholesterol and lipids but have also a key role as signaling molecules and in the modulation of epithelial cell proliferation, gene expression and metabolism. These homeostatic pathways, when disrupted, are able to promote local inflammation, systemic metabolic disorders and, ultimately, cancer. The effect of hydrophobic BAs, in particular, can be linked with cancer in several digestive (mainly oesophagus, stomach, liver, pancreas, biliary tract, colon) and extra-digestive organs (i.e. prostate, breast) through a complex series of mechanisms including direct oxidative stress with DNA damage, apoptosis, epigenetic factors regulating gene expression, reduced/increased expression of nuclear receptors (mainly farnesoid X receptor, FXR) and altered composition of gut microbiota, also acting as a common interface between environmental factors (including diet, lifestyle, exposure to toxics) and the molecular events promoting cancerogenesis. Primary prevention strategies (i.e. changes in dietary habits and lifestyle, reduced exposure to environmental toxics) mainly able to modulate gut microbiota and the epigenome, and the therapeutic use of hydrophilic BAs to counterbalance the negative effects of the more hydrophobic BAs might be, in the near future, part of useful tools for cancer prevention and management.

DOI: 10.5604/01.3001.0010.5501.

Keywords: Bile acids. Cancer. Microbiota. FXR. Environment. Epigenome. 

November, Vol. 16 (Suppl. 1), 2017: s4-s14

"Bile Acid Physiology"

Agostino Di Ciaula, Gabriella Garruti, Raquel Lunardi Baccetto, Emilio Molina-Molina, Leonilde Bonfrate, David Q.-H. Wang, Piero Portincasa

ABSTRACT 

The primary bile acids (BAs) are synthetized from cholesterol in the liver, conjugated to glycine or taurine to increase their solubility, secreted into bile, concentrated in the gallbladder during fasting, and expelled in the intestine in response to dietary fat. BAs are also bio-transformed in the colon to the secondary BAs by the gut microbiota, reabsorbed in the ileum and colon back to the liver, and minimally lost in the feces. BAs in the intestine not only regulate the digestion and absorption of cholesterol, triglycerides, and fatsoluble vitamins, but also play a key role as signaling molecules in modulating epithelial cell proliferation, gene expression, and lipid and glucose metabolismby activating farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) in the liver, intestine, muscle and brown adipose tissue. Recent studies have revealed the metabolic pathways of FXR and GPBAR-1 involved in the biosynthesis and enterohepatic circulation of BAs and their functions as signaling molecules on lipid and glucose metabolism.

DOI: 10.5604/01.3001.0010.5493

Keywords: Bile acids. Microbiota. FXR. Bile.

European Journal of Clinical Investigation

“Exercising the hepatobiliary‐gut axis. The impact of physical activity performance”

Emilio Molina‐Molina, Raquel Lunardi Baccetto,  David Q.‐H. Wang, Ornella de Bari,  Marcin Krawczyk, Piero Portincasa

ABSTRACT

Background
Physical inactivity puts the populations at risk of several health problems, while regular physical activity brings beneficial effects on cardiovascular disease, mortality and other health outcomes, including obesity, glycaemic control and insulin resistance. The hepatobiliary tract is greatly involved in several metabolic aspects which include digestion and absorption of nutrients in concert with intestinal motility, bile acid secretion and flow across the enterohepatic circulation and intestinal microbiota. Several metabolic abnormalities, including nonalcoholic fatty liver as well as cholesterol cholelithiasis, represent two conditions explained by changes of the aforementioned pathways.

Materials and Methods
This review defines different training modalities and discusses the effects of physical activity in two metabolic disorders, that is nonalcoholic fatty liver disease (NAFLD) and cholelithiasis. Emphasis is given to pathogenic mechanisms involving intestinal bile acids, microbiota and inflammatory status.

Results
A full definition of physical activity includes the knowledge of aerobic and endurance exercise, metabolic equivalent tasks, duration, frequency and intensity, beneficial and harmful effects. Physical activity influences the hepatobiliary‐gut axis at different levels and brings benefits to fat distribution, liver fat and gallbladder disease while interacting with bile acids as signalling molecules, intestinal microbiota and inflammatory changes in the body.

Conclusions
Several beneficial effects of physical activity are anticipated on metabolic disorders linking liver steatosis, gallstone disease, gut motility, enterohepatic circulation of signalling bile acids in relation to intestinal microbiota and inflammatory changes.

DOI: https://doi.org/10.1111/eci.12958

Keywords: bile acids, farnesoid X receptor, G protein–coupled bile acid receptor-1, gallstone disease, gut microbiota, nonalcoholic fatty liver disease

Magnetic Resonance in Medicine 2018;1–6.

“Sources of hepatic glycogen synthesis in mice fed with glucose or fructose as the sole dietary carbohydrate”

Ivana Jarak, Cristina Barosa, Fatima O. Martins, Joao C. P. Silva, Cristiano Santos, Getachew Debas Belew, Joao Rito, Ivan Viegas, Jose Teixeira, Paulo J. Oliveira, John G. Jones

ABSTRACT

Purpose
The positional analysis of hepatic glycogen enrichment from deuterated water (2H2O) by 2H NMR has been applied previously to resolve the contributions of glucose and fructose to glycogen synthesis in rodents fed a high sucrose diet. To further validate this method, this analysis was applied to mice fed with synthetic diets whose carbohydrate components consisted solely of either glucose or fructose.

Methods
Eight glucose‐fed and 12 fructose‐fed mice were given 2H2O followed by ad libitum feeding overnight. Mice were then euthanized, hepatic glycogen was isolated and derivatized to monoacetone glucose, and 2H‐enrichment of positions 2, 5, and 6S were measured by 2H NMR. From these data, the fraction of overnight glycogen appearance from the direct pathway and/or glycogen cycling and indirect pathway were estimated. Indirect pathway fractions were resolved into Krebs cycle and triose‐phosphate sources—the latter including contributions from fructose metabolism.

Results
After overnight feeding, the fraction of overnight glycogen appearance derived from direct pathway and/or glycogen cycling in glucose‐fed‐mice was 63 ± 1%. For the indirect pathway, Krebs cycle and triose‐phosphate sources contributed 22 ± 1% and 15 ± 1%, respectively. For fructose‐fed‐mice, glycogen appearance was dominated by triose‐phosphate sources (60 ± 2%) with lesser contributions from Krebs cycle (14 ± 1%) and direct and/or glycogen cycling (26 ± 2%).

Conclusions
2H NMR analysis of hepatic glycogen 2H enrichment from 2H2O provides realistic profiles of dietary glucose and fructose contributions to hepatic glycogen synthesis in mice fed with diets containing 1 or the other sugar as the sole carbohydrate source.

DOI: 10.1002/mrm.27378

International Review of Cell and Molecular Biology, Vol. 340, 2018, pg. 209-344

“Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases”

Carlotta Giorgi, Saverio Marchi, Ines C. M. Simoes, Ziyu Ren, Giampaolo Morciano, Mariasole Perrone, Paulina Patalas, Krawczyk, Sabine Borchard, Paulina Jędrak, Karolina Pierzynowska, Jędrzej Szymański, David Q.Wang, Piero Portincasa, Grzegorz Węgrzyn, Hans Zischka, Pawel Dobrzyn, Massimo Bonora, Jerzy Duszynski, Mariusz R. Wieckowski

ABSTRACT

Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS–mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.

Keywords: Age-related neurodegenerative disorders Aging Anti-ROS intervention Antioxidant defense Mitochondria Mitochondrial dysfunction–related pathologies ROS

Transplant Proc. 2018 Apr;50(3):714-718

“Graft Protection Against Cold Ischemia Preservation: An Institute George Lopez 1 and Histidine-tryptophan-ketoglutarate Solution Appraisal”

Panisello-Rosello, C. Castro-Benítez, A. Lopez, S. Balloji, E. Folch-Puy, R. Adam, and J. Roselló-Catafau

ABSTRACT

Cold storage of organs in preservation solutions, such as Institute George Lopez 1 (IGL-1) or histidine-tryptophan-ketoglutarate (HTK), is a mandatory step for organ transplantation. This preservation leads to an ischemic injury that affects the outcome of the organ. This article studies the liver graft eluate after organ recovery using IGL-1 or HTK solutions. We explore the influence of the volume used for washing out the liver and the consequences in the graft preservation when both solutions are used. Livers were washed out with different volumes of HTK and IGL-1 according to manufacturers' instructions and then preserved in both solutions for 24 hours at 4°C. Tissue and eluates were collected for subsequent analyses. We measured transaminases (aspartate aminotransferase and alanine aminotransferase), histology by hematoxylin/eosin staining, and red blood cell and hemoglobin counts, respectively. After washing out and cold storage, the IGL-1 processed livers showed better preservation than those with HTK solution; however, in this latter case, an important accumulation of erythrocytes was found when compared to IGL-1. These data were consistent with the higher hemoglobin and red blood cell counts observed for IGL-1 eluates after 24 hours. The volume used for washing out the organ depends on the composition and properties of the organ preservation solutions (ie, IGL-1 and HTK); this is an important factor for the graft cold preservation. The total volume used for washing out the graft should be considered because it has a direct impact on the total cost for clinical transplantations.

DOI: 10.1016/j.transproceed.2018.02.044