Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.     

Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology

Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states.     

Eosinophils in the pathogenesis of allergic airways disease

Eosinophils are traditionally thought to form part of the innate immune response against parasitic helminths acting through the release of cytotoxic granule proteins. However, they are also a central feature in asthma. From their development in the bone marrow to their recruitment to the lung via chemokines and cytokines, they form an important component of the inflammatory milieu observed in the asthmatic lung following allergen challenge. A wealth of studies has been performed in both patients with asthma and in mouse models of allergic pulmonary inflammation to delineate the role of eosinophils in the allergic response. Although the long-standing association between eosinophils and the induction of airway hyper-responsiveness remains controversial, recent studies have shown that eosinophils may also promote airway remodelling. In addition, emerging evidence suggests that the eosinophil may also serve to modulate the immune response. Here we review the highly co-ordinated nature of eosinophil development and trafficking and the evolution of the eosinophil as a multi-factoral leukocyte with diverse functions in asthma. Received 6 December 2006; received after revision 11 January 2007; accepted 15 February 2007     

Activation of cathepsin in fatty liver

Riassunto L'attività cateptica del fegato grasso ottenuto mediante trattamento parenterale con CCl₄ o con fosforo nel ratto è aumentata rispetto al normale. Nel normale, gli omogenati hanno una attività cateptica molto bassa, che aumenta di molte volte se si aggiunge al mezzo il Triton X-100. Nel fegato grasso, invece, si osserva una discreta attività cateptica già in assenza di Triton; questo determina un aumento dell'attività, ma in misura percentualmente minore che nel normale. In presenza di Triton, l'attività cateptica dell'omogenato di fegato grasso è superiore a quella del fegato normale. L'aumento dell'attività enzimatica non è quindi interamente attribuibile alla lesione delle particelle che contengono l'enzima.     

Immunogenicity of fatty acid anilides in rabbits and the pathogenesis of the Spanish toxic oil syndrome

Summary Fatty acid anilides, the major xenobiotic found in the cooking oils responsible for the Spanish toxic oil syndrome, are immunogenic for rabbits as ascertained by a skin test reaction, the characterization of specific antibodies against anilides and the immunofluorescent detection of anilide dependent antigens in tissue slices from treated animals.Acknowledgments. This work was supported by a grant from the Fondo de Investigaciones Sanitarias to the C.S.I.C. Programme on Toxic Oil Syndrome. We are indebted to Dr M. Studt and Dr E. Fernández-Alvarez, from the National Center for Organic Chemistry, C.S.I.C., for kindly providing the synthetic fatty acid anilides. We also wish to thank Prof. C. Gitler for helpful discussion.     

Lymphocyte-fibroblast interaction in the pathogenesis of inflammatory gingival disease

Zusammenfassung Eine morphometrische Analyse menschlicher, entzündeter Gingiva ergab im Vergleich zu normalem Bindegewebe 70% weniger Kollagenfasern, dreifach vergrösserte und pathologisch veränderte Fibroblasten und eine kleine Population charakteristischer Immunoblasten mit einer Zellansammlung, die zu 76% aus Zellen der Lymphozytenserie bestand. Die Grösse der Fibroblasten war positiv mit der steigenden Zahl der Lymphozyten korreliert. Diese Befunde weisen auf eine Immunreaktion mit zytotoxischen Auswirkungen auf Fibroblasten des gingivalen Bindegewebes hin.     

Immunogenicity of fatty acid anilides in rabbits and the pathogenesis of the Spanish toxic oil syndrome

Fatty acid anilides, the major xenobiotic found in the cooking oils responsible for the Spanish toxic oil syndrome, are immunogenic for rabbits as ascertained by a skin test reaction, the characterization of specific antibodies against anilides and the immunofluorescent detection of 'anilide dependent antigens' in tissue slices from treated animals.     

Activation of fatty acids in the liver in carbon tetrachloride poisoning

Zusammenfassung Bei CCl₄-Vergiftung zeigt die Leber eine vermehrte Aktivierung der Fettsäuren, die sich fast gleichzeitig mit der fettigen Infiltration kundgibt. Die Abnahme der Aktivierung äussert sich bereits 5 h nach der Vergiftung in statistisch signifikanter Weise. Zugabe von CCl₄ hemmtin vitro die Aktivierung von Palmitin- und Buttersäure.     

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system. The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing future disease-specific therapies. Received 24 April 2006; received after revision 3 July 2006; accepted 9 October 2006     

On the role of non-specific factors in the pathogenesis of infectious disease

Zusammenfassung Es wird einleitend darauf hingewiesen, dass mehr und mehr die Bedeutung von unspezifischen Faktoren für die Resistenz gegen Infektionen erkannt wird. Solche Faktoren können wohl auch in der Pathogenese von Infektionskrankheiten eine Rolle spielen, so zum Beispiel eine erhöhte Sensibilität gegen Endotoxin, die während den verschiedensten experimentellen Infektionen in Tieren nachgewiesen werden kann. An Hand von Experimenten an Mäusen wird dargestellt, in welchem Ausmass eine vorausgehende Impfung mit BCG den Ablauf einer nachfolgenden Infektion mitSalmonella typhimurium in verschiedenster Weise beeinflussen kann. Dies hängt weitgehend davon ab, ob grosse oder kleine Dosen zur Infektion verwendet werden.     

Polyunsaturated fatty acids and cardiovascular disease

Replacing saturated with polyunsaturated (PUFAs) rather than monounsaturated fatty acids or carbohydrates results in cardiovascular prevention over a wide range of intakes. The mechanisms by which PUFAs reduce cardiovascular risk are manifold, and the extent and precise nature of their activities is the subject of several investigations, spanning from in vitro mechanistic studies to human intervention trials. This article reviews the most up-to-date evidence of the association between PUFA consumption and reduced cardiovascular mortality.