- This medical progress review serves to frame an understanding of NAFLD for clinicians by outlining risk factors, prevalence, diagnostics, pathogenesis, and potential treatments. It suggested a few different means by which fat accumulates in the liver and that drug treatments may be the best means to treat NAFLD.
Black, Lucinda J., Peter Jacoby, Wendy Chan She Ping-Delfos, Trevor A. Mori, Lawrence J. Beilin, John K. Olynyk, Oyekoya T. Ayonrinde, et al. 2014. “Low Serum 25-hydroxyvitamin D Concentrations Are Associated with Non-alcoholic Fatty Liver Disease in Adolescents Independent of Adiposity.” Journal of Gastroenterology and Hepatology (February 1): n/a–n/a. doi:10.1111/jgh.12541. http://onlinelibrary.wiley.com/doi/10.1111/jgh.12541/abstract.
- Clinical study that investigates the role of Vitamin D deficiency in the progression of NAFLD. Found that individuals with NAFLD have lower serum 25-hydroxyvitamin D concentrations and therefore, Vitamin D supplementation may be a means of treating NAFLD.
Cohen, Jonathan C., Jay D. Horton, and Helen H. Hobbs. 2011. “Human Fatty Liver Disease: Old Questions and New Insights.” Science 332 (6037) ( 6–24): 1519–1523. doi:10.1126/science.1204265. http://www.sciencemag.org/content/332/6037/1519.
- Review article outlining the three major ways that fatty acids accumulate in hepatic cells; diet, de novo synthesis, and adipose tissue. Examined some of the major theories for how NAFLD progresses including a mutation in PNPLA3, adipose tissues releasing proinflammatory adipocytokines, and ER stress.
DeBosch, Brian J., Zhouji Chen, Jessica L. Saben, Brian N. Finck, and Kelle H. Moley. 2014. “Glucose Transporter 8 (GLUT8) Mediates Fructose-induced de Novo Lipogenesis and Macrosteatosis.” Journal of Biological Chemistry (February 11): jbc.M113.527002. doi:10.1074/jbc.M113.527002. http://www.jbc.org/content/early/2014/02/11/jbc.M113.527002.
- Examined the role of GLUT8, a selective fructose transporter. Discovered that GLUT8 is directly responsible for the transportation of fructose into hepatic cells and therefore, GLUT8 can serve as a primary target for reducing fat accumulation in the liver.
Della Corte, Claudia, Anna Alisi, Alessia Saccari, Rita De Vito, Andrea Vania, and Valerio Nobili. 2012. “Nonalcoholic Fatty Liver in Children and Adolescents: An Overview.” Journal of Adolescent Health 51 (4) (October): 305–312. doi:10.1016/j.jadohealth.2012.01.010. http://www.sciencedirect.com/science/article/pii/S1054139X12000213.
- Reviewed the current state of NAFLD in pediatric and adolescent populations. Outlined some basic understandings of the disease, disease mechanisms, and the failure of current diagnostic techniques.
Della Corte, Claudia, Daniela Liccardo, Antonella Mosca, Andrea Vania, and Valerio Nobili. 2013. “Non-alcoholic Fatty Liver Disease.” Paediatrics and Child Health 23 (12) (December): 529–534. doi:10.1016/j.paed.2013.08.003. http://www.sciencedirect.com/science/article/pii/S1751722213001996.
- Summarizes the current understanding of NAFLD in adolescent populations as well as some of the theories behind the progression of NAFLD, including the role of Toll-like Receptors and TNF-alpha.
Dubuquoy, Céline, Anne-Françoise Burnol, and Marthe Moldes. 2013. “PNPLA3, a Genetic Marker of Progressive Liver Disease, Still Hiding Its Metabolic Function?” Clinics and Research in Hepatology and Gastroenterology 37 (1) (February): 30–35. doi:10.1016/j.clinre.2012.06.014. http://www.sciencedirect.com/science/article/pii/S2210740112001969.
- Reviewed the current understanding of the PNPLA3 mutation. Described PNPLA3’s regulation by ChREBP and SREBP1c in response to glucose/insulin and outlined some of PNPLA3’s activity and structural components.
Dubuquoy, Céline, Céline Robichon, Françoise Lasnier, Clotilde Langlois, Isabelle Dugail, Fabienne Foufelle, Jean Girard, Anne-Françoise Burnol, Catherine Postic, and Marthe Moldes. 2011. “Distinct Regulation of adiponutrin/PNPLA3 Gene Expression by the Transcription Factors ChREBP and SREBP1c in Mouse and Human Hepatocytes.” Journal of Hepatology 55 (1) (July): 145–153. doi:10.1016/j.jhep.2010.10.024. http://www.sciencedirect.com/science/article/pii/S0168827810010858.
- The authors in this study found that SREBP1c is responsible for regulating PNPLA3 in humans and that ChREBP is primarily responsible for regulating PNPLA3 in mice.
Eberlé, Delphine, Bronwyn Hegarty, Pascale Bossard, Pascal Ferré, and Fabienne Foufelle. 2004. “SREBP Transcription Factors: Master Regulators of Lipid Homeostasis.” Biochimie 86 (11). Recent Advances in Lipid Metabolism and Related Disorders (November): 839–848. doi:10.1016/j.biochi.2004.09.018. http://www.sciencedirect.com/science/article/pii/S0300908404001658.
- A detailed investigation into SREBP transcription factors as well as the role of SREBP1c in the regulation of lipid metabolism.
Gentile, Christopher L., Melinda A. Frye, and Michael J. Pagliassotti. 2011. “Fatty Acids and the Endoplasmic Reticulum in Non-Alcoholic Fatty Liver Disease.” BioFactors (Oxford, England) 37 (1) (January): 8–16. doi:10.1002/biof.135. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080031/.
- The authors of this study examined the role of fatty acids in the promotion of endoplasmic reticulum stress. They concluded that fatty acids are responsible for causing endoplasmic reticulum stress and that ER stress can ultimately lead to hepatocyte cell death.
He, Shaoqing, Christopher McPhaul, John Zhong Li, Rita Garuti, Lisa Kinch, Nick V. Grishin, Jonathan C. Cohen, and Helen H. Hobbs. 2010. “A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis.” Journal of Biological Chemistry 285 (9) ( 2–26): 6706–6715. doi:10.1074/jbc.M109.064501. http://www.jbc.org/content/285/9/6706.
- This study focused on the I148M variant and created a homology model of the mutation using the heartleaf horsenettle patatin domain x-ray structure. The authors concluded that PNPLA3 functions as a triglyceride hydrolase.
Henao-Mejia, Jorge, Eran Elinav, Chengcheng Jin, Liming Hao, Wajahat Z. Mehal, Till Strowig, Christoph A. Thaiss, et al. 2012. “Inflammasome-mediated Dysbiosis Regulates Progression of NAFLD and Obesity.” Nature 482 (7384) (February 9): 179–185. doi:10.1038/nature10809. http://www.nature.com/nature/journal/v482/n7384/full/nature10809.html.
- Study of a protein complex called the “inflammasome” and how deficiencies in the inflammasome may contribute to the uncontrolled inflammatory reaction that leads to the progression of NAFLD to NASH.
Horton, Jay D., Joseph L. Goldstein, and Michael S. Brown. 2002. “SREBPs: Activators of the Complete Program of Cholesterol and Fatty Acid Synthesis in the Liver.” The Journal of Clinical Investigation 109 (9) (May 1): 1125–1131. doi:10.1172/JCI15593. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC150968/.
- The authors of this study focused on the transcription factor SREBP and found that it activates enzymes in the fatty acid biosynthetic pathway as well as enzymes that produce the confactor NADPH.
Huang, Yongcheng, Jonathan C. Cohen, and Helen H. Hobbs. 2011. “Expression and Characterization of a PNPLA3 Protein Isoform (I148M) Associated with Nonalcoholic Fatty Liver Disease.” Journal of Biological Chemistry 286 (43) ( 10–28): 37085–37093. doi:10.1074/jbc.M111.290114. http://www.jbc.org/content/286/43/37085.
- The authors of this study purified recombinant PNPLA3 from insect cells and studied the effects of the I148M mutation on enzyme activity. They found that the mutation decreased enzymatic activity and that PNPLA3 has a preference for the long-chain fatty acid, oleic acid.
Huang, Yongcheng, Shaoqing He, John Zhong Li, Young-Kyo Seo, Timothy F. Osborne, Jonathan C. Cohen, and Helen H. Hobbs. 2010. “A Feed-forward Loop Amplifies Nutritional Regulation of PNPLA3.” Proceedings of the National Academy of Sciences 107 (17) ( 4–27): 7892–7897. doi:10.1073/pnas.1003585107. http://www.pnas.org/content/107/17/7892.
- The authors of this study found that SREBP1c activates the transcription of PNPLA3 directly and by increasing fatty acid synthesis.
Hyysalo, Jenni, Peddinti Gopalacharyulu, Hua Bian, Tuulia Hyötyläinen, Marja Leivonen, Nabil Jaser, Anne Juuti, et al. 2014. “Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated with the I148M Variant in PNPLA3 and with Obesity.” Diabetes 63 (1) (January): 312–322. doi:10.2337/db13-0774.
- This research revealed that in mice overexpressing human PNPLA3 I148M circulating long-chain triglycerides were depleted. These results indicated that the PNPLA3 I148M mutant is impeding the hydrolysis of these triglycerides on the surface of lipid droplets and preventing their export from the liver.
Ingraham, Holly A. 2011. “Metabolism: A Lipid for Fat Disorders.” Nature 474 (7352) (June 23): 455–456. doi:10.1038/474455a. http://www.nature.com/nature/journal/v474/n7352/full/474455a.html.
- This is a News&Views report on the research of Lee et al. on DLPC’s use as a potential treatment for NAFLD.
Jablonski, K L, A Jovanovich, J Holmen, G Targher, K McFann, J Kendrick, and M Chonchol. 2013. “Low 25-hydroxyvitamin D Level Is Independently Associated with Non-alcoholic Fatty Liver Disease.” Nutrition, Metabolism, and Cardiovascular Diseases: NMCD 23 (8) (August): 792–798. doi:10.1016/j.numecd.2012.12.006.
- Clinical study which displays that decreased serum 25-hydoxyvitamin levels are independently associated with NAFLD.
Kwok, Ryan M., Dawn M. Torres, and Stephen A. Harrison. 2013. “Vitamin D and Nonalcoholic Fatty Liver Disease (NAFLD): Is It More Than Just an Association?” Hepatology 58 (3) (September 1): 1166–1174. doi:10.1002/hep.26390. http://onlinelibrary.wiley.com/doi/10.1002/hep.26390/abstract.
- This study reviewed the link between decreased levels of Vitamin D and NAFLD. The authors suggest that Vitamin D replacement may be a suitable treatment.
Lee, Jae Man, Yoon Kwang Lee, Jennifer L. Mamrosh, Scott A. Busby, Patrick R. Griffin, Manish C. Pathak, Eric A. Ortlund, and David D. Moore. 2011. “A Nuclear-receptor-dependent Phosphatidylcholine Pathway with Antidiabetic Effects.” Nature 474 (7352) (June 23): 506–510. doi:10.1038/nature10111. http://www.nature.com/nature/journal/v474/n7352/abs/nature10111.html.
- The authors of this study found that dilauroyl phosphatidylcholine decreases hepatic steatosis by acting as a ligand on LRH-1. They show that DLPC treatment lowers hepatic triglycerides and serum glucose concentrations.
Li, Songtao, Fanyu Meng, Xilu Liao, Yemei Wang, Zongxiang Sun, Fuchuan Guo, Xiaoxia Li, Man Meng, Ying Li, and Changhao Sun. 2014. “Therapeutic Role of Ursolic Acid on Ameliorating Hepatic Steatosis and Improving Metabolic Disorders in High-fat Diet-induced Non-alcoholic Fatty Liver Disease Rats.” PloS One 9 (1): e86724. doi:10.1371/journal.pone.0086724.
- The authors of this study identify Ursolic Acid as a potential treatment against NAFLD through a PPARα-dependent pathway.
Lustig, Robert H. 2013. “Fructose: It’s ‘Alcohol Without the Buzz’.” Advances in Nutrition: An International Review Journal 4 (2) ( 3–1): 226–235. doi:10.3945/an.112.002998. http://advances.nutrition.org/content/4/2/226.
- This review analyzed the role of fructose metabolism in the promotion of hepatic steatosis. It indicated that fructose activates both ChREBP and SREBP-1c leading to increased de novo lipogenesis and hepatic steatosis.
McMahan, Rachel H., Xiaoxin X. Wang, Lin Ling Cheng, Tibor Krisko, Maxwell Smith, Karim El Kasmi, Mark Pruzanski, et al. 2013. “Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and Improves Nonalcoholic Fatty Liver Disease.” Journal of Biological Chemistry 288 (17) ( 4–26): 11761–11770. doi:10.1074/jbc.M112.446575. http://www.jbc.org/content/288/17/11761.
- The authors of this study showed that activation of bile acid receptors, FXR/TGR5, decreases inflammatory cytokines and therefore, stops the progression of NAFLD to NASH.
Perito, Emily R, Luis A Rodriguez, and Robert H Lustig. 2013. “Dietary Treatment of Nonalcoholic Steatohepatitis.” Current Opinion in Gastroenterology 29 (2): 170–76. doi:10.1097/MOG.0b013e32835ca11d.
- This review articles was used for the image of the impact of dietary fats and fructose on hepatic steatosis and NASH.
Pfluger, Paul T., Daniel Herranz, Susana Velasco-Miguel, Manuel Serrano, and Matthias H. Tschöp. 2008. “Sirt1 Protects Against High-fat Diet-induced Metabolic Damage.” Proceedings of the National Academy of Sciences 105 (28) ( 7–15): 9793–9798. doi:10.1073/pnas.0802917105. http://www.pnas.org/content/105/28/9793.
- This study concludes that Sirt1 is responsible for activating antioxidant proteins as well as decreasing proinflammatory cytokines, thereby decreasing the inflammatory environment and slowing the progression to NASH.
Qiao, Aijun, Jichao Liang, Yaojun Ke, Chenghong Li, Ying Cui, Lian Shen, Huabing Zhang, et al. 2011. “Mouse Patatin-like Phospholipase Domain-containing 3 Influences Systemic Lipid and Glucose Homeostasis.” Hepatology (Baltimore, Md.) 54 (2) (August): 509–521. doi:10.1002/hep.24402.
- The authors of this study found that SREBP1c regulates PNPLA3 which acts a lipogenic gene to promote TAG synthesis.
Romeo, Stefano, Julia Kozlitina, Chao Xing, Alexander Pertsemlidis, David Cox, Len A. Pennacchio, Eric Boerwinkle, Jonathan C. Cohen, and Helen H. Hobbs. 2008. “Genetic Variation in PNPLA3 Confers Susceptibility to Nonalcoholic Fatty Liver Disease.” Nature Genetics 40 (12) (December): 1461–1465. doi:10.1038/ng.257. http://www.nature.com/ng/journal/v40/n12/full/ng.257.html.
- This is one of the first studies identifying variants of PNPLA3. The authors suggest that these genetic variants contribute to hepatic fat content.
Roth, Christian L, Clinton T Elfers, Dianne P Figlewicz, Susan J Melhorn, Gregory J Morton, Andrew Hoofnagle, Matthew M Yeh, James E Nelson, and Kris V Kowdley. 2012. “Vitamin D Deficiency in Obese Rats Exacerbates Nonalcoholic Fatty Liver Disease and Increases Hepatic Resistin and Toll-like Receptor Activation.” Hepatology (Baltimore, Md.) 55 (4) (April): 1103–1111. doi:10.1002/hep.24737.
- This authors of this study developed a mouse model to study decreased Vitamin D levels. Then they investigated how TLRs lead to the development of NAFLD and IR.
Shao, Di, Jessica L. Fry, Jingyan Han, Xiuyun Hou, David R. Pimentel, Reiko Matsui, Richard A. Cohen, and Markus M. Bachschmid. 2014. “A Redox-resistant Sirtuin-1 Mutant Protects Against Hepatic Metabolic and Oxidant Stress.” Journal of Biological Chemistry 289 (11) ( 3–14): 7293–7306. doi:10.1074/jbc.M113.520403. http://www.jbc.org/content/289/11/7293.
- The authors of this study developed a mouse model of mutated Sirt1 to investigate the role of oxidative stress on Sirt1 activity. Under conditions of oxidative stress, Sirt1’s activity is decreased which decreases its ability to reduce inflammation.