The gallstone Lith gene map has been updated which lists
The gallstone (Lith) gene map has been updated, which lists all known genetic loci that confer gallstone susceptibility, as well as candidate genes in inbred strains of mice. Understanding molecular genetics of gallstone disease in mice will push for the identification of human Lith genes. In addition, genetic analysis of Lith genes in mouse models will open the avenue for searching for the orthologous human Lith genes and for exploring their cholelithogenic effects in humans. These studies should lead to the discovery of lithogenic actions of each of the Lith genes, providing novel insights into the molecular and cellular mechanisms that determine the formation of cholesterol gallstones. More importantly, the ABCG5/G8-dependent and the ABCG5/G8-independent pathways play critical roles in the regulation of hepatic cholesterol secretion, suggesting that both pathways are potential therapeutic targets for gallstones. Determining the molecular and cellular mechanisms on the formation of cholesterol-supersaturated bile may lead to novel therapeutic approaches through modulating both the ABCG5/G8-dependent and the ABCG5/G8-independent pathways for the prevention and the treatment of cholesterol gallstone disease that affects millions in westernized societies.
Conflict of interest
Acknowledgements This work was supported in part by research grants DK101793 and DK106249 (to DQ-HW), both from the National Institutes of Health (US Public Health Service).
Introduction Alcohol consumption leads to damage in multiple organs, including liver injury, pancreatitis, adipose inflammation, cardiomyopathy, neurotoxicity, muscle loss, impaired immune functions, endocrine and fetal abnormalities, and osteoporosis. Among alcohol-induced tissue injuries, alcoholic liver disease (ALD) is the most common and a major health problem worldwide, claiming two million lives annually. Decades of work from many investigators has enriched our understanding of ALD pathogenesis and mechanisms. The spectrum of ALD is characterized by hepatic steatosis, cell death, and fibrosis, with a small portion of alcoholics eventually developing cirrhosis and liver cancer. Despite progress in ALD research, there is no successful treatment for ALD currently available. Alcoholic steatosis, occurring in more than 95% of alcohol drinkers, is characterized by the accumulation of excess lipid droplets (LDs) in the beta amyloid of hepatocytes. Steatosis, the initial ALD trigger, sensitizes hepatocytes to other cellular stresses or toxic factors, such as tumor necrosis factor-α (TNF-α), and promotes ALD pathogenesis. Importantly, studies in rodents and humans demonstrate that chronic alcohol consumption decreases adipose tissue mass because of increased adipocyte lipolysis, which increases hepatic reverse transport of free fatty acids (FFAs) and thus may contribute to liver steatosis and injury. These early findings suggest a critical cross-talk between adipose tissue and liver, in which alcohol-induced changes in adipose tissue can influence ALD pathogenesis. The purpose of this review is to summarize and discuss the underlying possible mechanisms linking adipose tissue lipodystrophy to alcoholic hepatic steatosis and ALD. Particularly, we will discuss the potential role of adipose autophagy in adipose pathophysiology and its impact on ALD.
Autophagy Autophagy is a highly conserved, genetically programmed lysosomal degradation pathway. To date, there have been more than 40 autophagy-related (Atg) genes identified that regulate this process. Autophagy generally involves five key steps, as illustrated in Fig. 1. The process begins with initiation, which is regulated by the Unc-51 like kinase 1 (ULK1)-FAK family-interacting protein of 200 kDa (FIP200)-Atg13 complex. This complex is negatively regulated by the nutrient sensor, mechanistic target of rapamycin complex 1 (mTORC1), and positively regulated by the energy sensor, AMP-activated protein kinase. The second step is nucleation, which requires the endoplasmic reticulum (ER)-resident SNARE protein syntaxin 17 (STX17). STX17 recruits Atg14L to the rough ER or ER-mitochondria contact site, and Atg14L then recruits Beclin 1 and class III phosphoinositide 3-kinase vacuolar protein sorting 34 (Vps34) to the autophagosome initiation site on the rough ER. Vps34 is a mammalian class-III phosphatidylinositol 3-phosphate kinase that promotes the generation of phosphatidylinositol 3-phosphate (PI3-P). PI3-P recruits PI3-P effectors, such as double FYVE domain-containing protein 1 and WD-repeat interacting protein with phosphoinositide 1 and 2, to initiate autophagosome biogenesis. Activating molecule in Beclin1-regulated autophagy, UV irradiation resistance-associated gene, and Bif-1/Endophilin B1 positively regulate this complex, whereas B-cell lymphoma 2, B-cell lymphoma-extra large, Run domain Beclin1-interacting and cysteine-rich domain-containing protein, AKT/protein kinase B, and epidermal growth factor receptor negatively regulate this complex. The third step in the process is elongation, in which the two ubiquitin-like conjugation systems, the Atg7 (E1 ubiquitine-activating enzyme-like)-Atg3 (E2 ubiquitine-conjugating enzyme-like)-microtubule-associated light chain (LC3) and Atg12-Atg5-Atg16L1 complexes (E3 ubiquitine ligase-like), regulate phosphatidylethanolamine conjugation with LC3 (called LC3-II). This process expands the autophagosome membrane. Atg9, the only Atg protein with transmembrane domains, also delivers membranes from trans-Golgi network/endosomes to the site of autophagosome biogenesis in a ULK1- and Vps34-dependent manner to promote the elongation of the autophagosome membrane. It should be noted that the Atg12-Atg5-Atg16L complex generally transiently attaches to the autophagosomal membranes and is later dissociated. This is in contrast with LC3-II, which is relatively stable on the autophagosome membranes until fusion of the autophagosomes with lysosomes. The fourth step is closure. The mechanisms by which the autophagosome membranes fuse with each other and eventually form a complete enclosed double membrane vesicle are still not completely understood. However, work from Dr. Ohsumi\'s lab has revealed that the LC3-II protein possesses a hemifusion function in vitro, which may help to tether the autophagosome membranes, resulting in eventual closure of the autophagosome. It should be noted that PI3-P is also dephosphorylated locally by the phosphatase myotubularin-related protein 3 upon closure of the autophagosomes. Finally, autophagosomes fuse with lysosomes/endosomes to form autolysosomes, a process that is mediated by Ras-related protein 7 (Rab7), lysosome-associated membrane protein 1/2, and STX17. After fusion, the LC3-II on outer membrane is deconjugated from the autolysosomal membrane by Atg4B, and the LC3-II on inner membrane is degraded together with the autophagosome cargo by lysosomal proteases.