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Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases
Open accessAbstract
NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.
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“For instance, in cases of concurrent diabetes and insulin resistance, oxidative stress in other tissues due to hyperglycaemia may compound lipotoxicity in the liver.34”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [34]
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InfluentialSelf-citationFGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis
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Self-citationLotta, L. A., Gulati, P., Day, F. R., Payne, F., Ongen, H., van de Bunt, M., Gaulton, K. J., Eicher, J. D., Sharp, S. J., Luan, J., et al. (2016) · Nature Genetics · doi:10.1038/ng.3714 · Cited by 599
Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
Markan, K. R., Naber, M. C., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M., & Potthoff, M. J. (2014) · Diabetes · doi:10.2337/db14-0595 · Cited by 590 · cited 1×
“Mice lacking hepatic FGF21 are prone to developing glucose intolerance when placed on a high-fat diet (Markan et al., 2014), whereas FGF21 transgenic mice have enhanced glucose tolerance (Zhang et al., 2012).”
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585 · cited 1×
“Kumashiro et al. studied determinants of insulin resistance in a cohort of patients undergoing bariatric surgery (Kumashiro et al., 2011).”
Self-citationBuch, S., Stickel, F., Trépo, E., Way, M., Herrmann, A., Nischalke, H. D., Brosch, M., Rosendahl, J., Berg, T., Ridinger, M., et al. (2015) · Nature Genetics · doi:10.1038/ng.3417 · Cited by 565 · cited 1×
“This polymorphism is also associated with fibrosis in alcoholic liver disease (Buch et al., 2015) and chronic hepatitis C (Thabet et al., 2016), suggesting that this pathway could contain therapeutic targets for several liver diseases.”
Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K. W., Shi, J., Brocker, C. N., Desai, D., Amin, S. G., Bisson, W. H., et al. (2015) · Nature Communications · doi:10.1038/ncomms10166 · Cited by 559
Uyeda, K., & Repa, J. J. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.06.008 · Cited by 538
FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss
Owen, B. M., Ding, X., Morgan, D. A., Coate, K. C., Bookout, A. L., Rahmouni, K., Kliewer, S. A., & Mangelsdorf, D. J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.012 · Cited by 523 · cited 1×
“This effect appears to be mediated centrally via hypothalamic receptors and activation of the sympathetic nervous system (Owen et al., 2014).”
Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico
Williams, A. L., Jacobs, S. B. R., Churchhouse, C. L., Burtt, N. P., Florez, J. C., Altshuler, D., Ripke, S., Manning, A. K., Neale, B. M., Reich, D., et al. (2013) · Nature · doi:10.1038/nature12828 · Cited by 508
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“Following a meal, the relatively high concentrations of insulin within the portal vein ( 33 peripheral vein) directly activate hepatic insulin receptor tyrosine kinase (IRTK) activity, initiating a coordinated relay of intracellular signals (Figure 1) (Samuel and Shulman, 2012).”
InfluentialSelf-citationSinha, R., Dufour, S., Petersen, K. F., LeBon, V., Enoksson, S., Ma, Y.-Z., Savoye, M., Rothman, D. L., Shulman, G. I., & Caprio, S. (2002) · Diabetes · doi:10.2337/diabetes.51.4.1022 · Cited by 495 · cited 1×
“…studies observed that ectopic, intramyocellular lipid (IMCL) was closely associated muscle insulin resistance in healthy, young, sedentary lean individuals (Krssak et al., 1999) and non-obese, non-diabetic, but insulin-resistant adults (Perseghin et al., 1999) and children (Sinha et al., 2002).”
Self-citationSharma, A. M., & Staels, B. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1268 · Cited by 483 · cited 22×
“LY2405319, an FGF21 variant, was tested in subjects with T2D.”
InfluentialHarrison, S. A., Fecht, W., Brunt, E. M., & Neuschwander‐Tetri, B. A. (2009) · Hepatology · doi:10.1002/hep.22575 · Cited by 470
Luukkonen, P. K., Zhou, Y., Sädevirta, S., Leivonen, M., Arola, J., Orešič, M., Hyötyläinen, T., & Yki-Järvinen, H. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.01.002 · Cited by 461
Mortality in the United States, 2024
Xu, J., Murphy, S. L., Kochanek, K. D., & Arias, E. (2026) · doi:10.15620/cdc/174641 · Cited by 461
Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis
Armstrong, M. J., Hull, D., Guo, K., Barton, D., Hazlehurst, J. M., Gathercole, L. L., Nasiri, M., Yu, J., Gough, S. C., Newsome, P. N., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.08.038 · Cited by 456
Savage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447 · cited 15×
“Fructose is metabolized almost exclusively by the liver, and therefore ingested fructose is funneled into the liver and mostly metabolized to triglycerides by DNL (Herman and Samuel, 2016).”
InfluentialMechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice
Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L., & Shulman, G. I. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8456 · Cited by 443 · cited 2×
“Lipodystrophic mice have a similar phenotype, and fat transplantation rescued thesemice by allowing a redistribution of lipids from ectopic sites to transplanted adipose tissue and normalization of insulin action (Kim et al., 2000).”
Self-citationEndocrine fibroblast growth factors 15/19 and 21: from feast to famine
Potthoff, M. J., Kliewer, S. A., & Mangelsdorf, D. J. (2012) · Genes & Development · doi:10.1101/gad.184788.111 · Cited by 442 · cited 1×
“More than 50 years ago, Levine and Fritz (1956), and subsequently Prager et al. (1987), proposed that insulin inhibited hepatic glucose production indirectly, via action at peripheral sites.”
Nazare, J., Smith, J. D., Borel, A., Haffner, S. M., Balkau, B., Ross, R., Massien, C., Alméras, N., & Després, J. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.035758 · Cited by 440
Subcutaneous Oxyntomodulin Reduces Body Weight in Overweight and Obese Subjects
Wynne, K., Park, A. J., Small, C. J., Patterson, M., Ellis, S. M., Murphy, K. G., Wren, A. M., Frost, G. S., Meeran, K., Ghatei, M. A., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.8.2390 · Cited by 435 · cited 1×
“Though small clinical studies have suggested that oxyntomodulin may be effective for weight loss (Wynne et al., 2005), clinical studies of dual GLP1R/GCGR agonists or triple GLP1R/ GIPR/GCGR have not been reported as of this writing.”
Dietary Sugar and Body Weight: Have We Reached a Crisis in the Epidemic of Obesity and Diabetes?
Bray, G. A., & Popkin, B. M. (2014) · Diabetes Care · doi:10.2337/dc13-2085 · Cited by 432 · cited 1×
“Some have implicated a specific increase in sugar consumption (Bray and Popkin, 2014).”
FGF15/19 Regulates Hepatic Glucose Metabolism by Inhibiting the CREB-PGC-1α Pathway
Potthoff, M. J., Boney-Montoya, J., Choi, M., He, T., Sunny, N. E., Satapati, S., Suino-Powell, K., Xu, H. E., Gerard, R. D., Finck, B. N., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.019 · Cited by 431 · cited 2×
“, 2011) and decreasing expression of gluconeogenic (Potthoff et al., 2011) and lipogenic enzymes (Bhatnagar et al.”
Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease
Petersen, K. F., Dufour, S., Hariri, A., Nelson-Williams, C., Foo, J. N., Zhang, X.-M., Dziura, J., Lifton, R. P., & Shulman, G. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907295 · Cited by 428 · cited 2×
“Multiple polymorphisms in ApoC3 (Peter et al., 2012; Petersen et al., 2010; Zhang et al., 2016) associated with NAFLD may increase plasma ApoC3 concentrations, which in turn inhibits lipoprotein lipase activity, leading to fasting and postprandial hypertriglyceridemia and prediposing lean individuals to NAFLD and insu…”
Self-citationWei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200797109 · Cited by 426
Kelley, D. E., McKolanis, T. M., Hegazi, R. A. F., Kuller, L. H., & Kalhan, S. C. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00117.2003 · Cited by 426 · cited 5×
“Mortality in the United States, 2015.”
InfluentialBile Acids as Hormones: The FXR-FGF15/19 Pathway
Kliewer, S. A., & Mangelsdorf, D. J. (2015) · Digestive Diseases · doi:10.1159/000371670 · Cited by 424 · cited 1×
“However, FXR also regulates the expression of numerous metabolic pathways, including gluconeogenesis and lipogenesis (Kliewer and Mangelsdorf, 2015).”
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · cited 2×
“Increases in visceral adipose tissue (VAT) have been associated with dyslipidemia (Després et al., 1990), insulin resistance (Couillard et al.”
The starvation hormone, fibroblast growth factor-21, extends lifespan in mice
Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., Xiao, G., Potthoff, M. J., Wei, W., Wan, Y., et al. (2012) · eLife · doi:10.7554/elife.00065 · Cited by 420
Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans
Szendroedi, J., Yoshimura, T., Phielix, E., Koliaki, C., Marcucci, M., Zhang, D., Jelenik, T., Müller, J., Herder, C., Nowotny, P., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409229111 · Cited by 415
Self-citationMiyazaki, M., Flowers, M. T., Sampath, H., Chu, K., Otzelberger, C., Liu, X., & Ntambi, J. M. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.014 · Cited by 414
Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L. J., Baron, M., Lucas, A., Tailleux, A., Hum, D. W., et al. (2013) · Hepatology · doi:10.1002/hep.26461 · Cited by 414 · cited 2×
“The PPARa effects may promote fatty acid oxidation (Pawlak et al., 2015), while the PPARd effects possibly decrease DNL and suppress inflammation (Bojic and Huff, 2013; Staels et al., 2013).”
Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice
Pocai, A., Carrington, P. E., Adams, J. R., Wright, M., Eiermann, G., Zhu, L., Du, X., Petrov, A., Lassman, M. E., Jiang, G., et al. (2009) · Diabetes · doi:10.2337/db09-0278 · Cited by 409 · cited 2×
“In fat-fed rodents, a long-acting dual GLP1R/ GCGR agonist resulted in greater weight loss than a pure GLP1R agonist, with improvements in hepatic steatosis and changes in gene expression consistent with increased hepatic lipid oxidation (Pocai et al., 2009).”
Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect
Sisley, S. R., Gutiérrez‐Aguilar, R., Scott, M. M., D’Alessio, D. A., Sandoval, D. A., & Seeley, R. J. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72434 · Cited by 405
Choi, C. S., Savage, D. B., Kulkarni, A., Yu, X. X., Liu, Z.-X., Morino, K., Kim, S., Distefano, A., Samuel, V. T., Neschen, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704213200 · Cited by 383 · cited 2×
“However, decreasing hepatic and adipose DGAT2 expressionwith specific ASOs lowers diacylglycerol content (and PKCε activity) by inhibiting lipogenesis and reverses diet-induced hepatic insulin resistance (Choi et al., 2007).”
Self-citationMahdessian, H., Taxiarchis, A., Popov, S., Silveira, A., Franco-Cereceda, A., Hamsten, A., Eriksson, P., & van't Hooft, F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1323785111 · Cited by 369 · cited 2×
“Polymorphisms in transmembrane 6 superfamily member 2 (rs58542926) have also been associated with NAFLD (Mahdessian et al., 2014).”
Lazo, M., Solga, S. F., Horska, A., Bonekamp, S., Diehl, A. M., Brancati, F. L., Wagenknecht, L. E., Pi-Sunyer, F. X., Kahn, S. E., Clark, J. M., et al. (2010) · Diabetes Care · doi:10.2337/dc10-0856 · Cited by 367 · cited 1×
“These results have been replicated by other hypocaloric feeding studies (Lazo et al., 2010; Lim et al., 2011).”
Schell, J. C., Olson, K. A., Jiang, L., Hawkins, A. J., Van Vranken, J. G., Xie, J., Egnatchik, R. A., Earl, E. G., DeBerardinis, R. J., & Rutter, J. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.026 · Cited by 363 · cited 1×
“And loss of MPCmay be associated with oncogenesis, chemo-resistance, and poor survival in patients with some solid tumors (Schell et al., 2014; Zhong et al., 2015).”
Singal, A. G., Manjunath, H., Yopp, A. C., Beg, M. S., Marrero, J. A., Gopal, P., & Waljee, A. K. (2014) · The American Journal of Gastroenterology · doi:10.1038/ajg.2013.476 · Cited by 360 · cited 1×
“A common SNP (rs738409, I148M) in the lipid droplet protein patatin-like phospholipase domain-containing protein 3 (PNLPA3, also called adiponutrin) has been associated with NAFLD and fibrosis (Romeo et al., 2008; Singal et al., 2014).”
A Mouse Model of Hepatocellular Carcinoma
Nicholes, K., Guillet, S., Tomlinson, E., Hillan, K., Wright, B., Frantz, G. D., Pham, T. A., Dillard-Telm, L., Tsai, S. P., Stephan, J.-P., et al. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)61177-7 · Cited by 359 · cited 1×
“However, the therapeutic use of FGF19 itself has been limited by the potential for ectopically produced FGF19 to induce hepatocellular carcinoma (Nicholes et al., 2002).”
Mattar, S. G., Velcu, L. M., Rabinovitz, M., Demetris, A. J., Krasinskas, A. M., Barinas‐Mitchell, E., Eid, G. M., Ramanathan, R. C., Taylor, D. S., & Schauer, P. R. (2005) · Annals of Surgery · doi:10.1097/01.sla.0000179652.07502.3f · Cited by 341 · cited 1×
“Mattar et al. (2005) performed a similar study in subjects undergoing RYGB.”
Kim, D., & Kim, W. R. (2017) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2016.08.028 · Cited by 341 · cited 1×
“Globally, the rates of NAFLD in non-obese patients average between 10% and 30% in both Western and Eastern countries (Kim and Kim, 2017).”
Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Ladenson, P. W., Kristensen, J. D., Ridgway, E. C., OLSSON, A. G., Carlsson, B., Klein, I. L., Baxter, J. D., & Angelin, B. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0905633 · Cited by 338 · cited 1×
“Indeed, KB-2115 has been shown to be very efficacious in treating hyperlipidemia (Ladenson et al., 2010).”
du Plessis, J., van Pelt, J. F., Korf, H., Mathieu, C., der Schueren, B. V., Lannoo, M., Oyen, T., Topal, B., Fetter, G., Nayler, S., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.044 · Cited by 337 · cited 1×
“Specific changes in adipose tissue gene expression have also been associated with the development of NASH (du Plessis et al., 2015).”
Younossi, Z., & Henry, L. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.03.005 · Cited by 334 · cited 1×
“However, nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as the most common chronic liver disease (Younossi and Henry, 2016).”
Aging and adipose tissue: potential interventions for diabetes and regenerative medicine
Palmer, A. K., & Kirkland, J. L. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.02.013 · Cited by 324 · cited 1×
“Aging also impairs subcutaneous adipose tissue function, possibly due to the accumulation of senescent adipocytes and impaired pre-adipocyte development, with increases in ectopic lipid accumulation in VAT, liver, and skeletal muscle (Palmer and Kirkland, 2016).”
Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase
Kumari, M., Schoiswohl, G., Chitraju, C., Paar, M., Cornaciu, I., Rangrez, A. Y., Wongsiriroj, N., Nagy, H. M., Ivanova, P. T., Scott, S. A., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.008 · Cited by 313 · cited 1×
“PNPLA3 has dual functions as a triacylglycerol hydrolase and as an acylglycerol transacylase (Kumari et al., 2012), but the mechanism by which this polymorphism—which attenuates the hydrolase activity (Pingitore et al., 2014)—increases liver fat is still unclear.”
Effect of aerobic exercise training dose on liver fat and visceral adiposity
Keating, S. E., Hackett, D. A., Parker, H. M., O’Connor, H. T., Gerofi, J. A., Sainsbury, A., Baker, M. K., Chuter, V. H., Caterson, I. D., George, J., et al. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.022 · Cited by 313 · cited 1×
“Inactive obese patients who were randomized to several aerobic exercise programs also had modest reductions in liver fat, independent of weight changes (Keating et al., 2015).”
Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier
Divakaruni, A. S., Wiley, S. E., Rogers, G. W., Andreyev, A. Y., Petrosyan, S., Loviscach, M., Wall, E. A., Yadava, N., Heuck, A. P., Ferrick, D. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303360110 · Cited by 308 · cited 1×
“These proteins were discovered to be inhibited by TZD compounds and putatively mediate some of the insulin-sensitizing effects of these drugs; decreased mitochondrial pyruvate oxidation may promote AMPK-mediated muscle glucose uptake (Divakaruni et al., 2013).”
Juárez, R. G. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26991 · Cited by 303
Abdominal obesity: a marker of ectopic fat accumulation
Smith, U. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81507 · Cited by 298 · cited 1×
“However, many now consider VAT as another ectopic site for lipids when subcutaneous adipose tissue capacity is exceeded (Cuthbertson et al., 2017; Jensen, 2008; Smith, 2015).”
Klein, S., Mittendorfer, B., Eagon, J. C., Patterson, B. W., Grant, L. M., Feirt, N. M., Seki, E., Brenner, D. A., Korenblat, K., & McCrea, J. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.01.042 · Cited by 292 · cited 1×
“However, actual histological improvements in inflammation and fibrosis were not evident (Klein et al., 2006).”
Zhang, S., Wang, J., Liu, Q., & Harnish, D. C. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.025 · Cited by 290
Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase–1
Jiang, G., Li, Z., Liu, F., Ellsworth, K. P., Dallas-Yang, Q., Wu, M. S., Ronan, J., Esau, C., Murphy, C., Szalkowski, D., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23962 · Cited by 289 · cited 2×
“SCD1 ASO therapy protected mice against NAFLD on a high-fat diet with several changes associated with increased energy expenditure (Jiang et al., 2005).”
Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice
Tao, H., Zhang, Y., Zeng, X., Shulman, G. I., & Jin, S. (2014) · Nature Medicine · doi:10.1038/nm.3699 · Cited by 288
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“Subsequent studies (Lewis et al., 1996; Rebrin et al., 1996) postulated that these indirect effects of insulin to suppress he- 2 Cell Metabolism 27, January 9, 2017 patic glucose production weremediated by suppression of white adipose tissue (WAT) lipolysis, which Bergman hypothesized reflected…”
Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis
Li, J. Z., Huang, Y., Karaman, R., Ivanova, P. T., Brown, H. A., Roddy, T. P., Castro‐Perez, J. M., Cohen, J. C., & Hobbs, H. H. (2012) · Journal of Clinical Investigation · doi:10.1172/jci65179 · Cited by 287 · cited 1×
“These results have been replicated by other hypocaloric feeding studies (Lazo et al., 2010; Lim et al., 2011).”
Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R., Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520686113 · Cited by 287 · cited 2×
“With chronic treatment, ND-630 was safe and effective in decreasing hepatic and plasma lipid concentration and improving glucose metabolism in both high-sucrose- and high-fat-fed SpragueDawley rats as well as diabetic ZDF rats (Harriman et al., 2016).”
Mao, J., DeMayo, F. J., Li, H., Abu-Elheiga, L., Gu, Z., Shaikenov, T. E., Kordari, P., Chirala, S. S., Heird, W. C., & Wakil, S. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603115103 · Cited by 285 · cited 2×
“Mice lacking hepatic FGF21 are prone to developing glucose intolerance when placed on a high-fat diet (Markan et al., 2014), whereas FGF21 transgenic mice have enhanced glucose tolerance (Zhang et al.”
Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats
Perry, R. J., Zhang, D., Zhang, X.-M., Boyer, J. L., & Shulman, G. I. (2015) · Science · doi:10.1126/science.aaa0672 · Cited by 283
Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus
Maggs, D. G., Buchanan, T. A., Burant, C., Cline, G. W., Gumbiner, B., Hsueh, W. A., Inzucchi, S., Kelley, D., Nolan, J., Olefsky, J. M., et al. (1998) · Annals of Internal Medicine · doi:10.7326/0003-4819-128-3-199802010-00002 · Cited by 283
Self-citationEffect of troglitazone on body fat distribution in type 2 diabetic patients.
Mori, Y., Murakawa, Y., Okada, K., Horikoshi, H., Yokoyama, J., Tajima, N., & Ikeda, Y. (1999) · Diabetes Care · doi:10.2337/diacare.22.6.908 · Cited by 281 · cited 2×
“, 2002), decrease visceral adipose tissue mass (Miyazaki et al., 2002; Mori et al., 1999), and improve hepatic and muscle insulin resistance (Mayerson et al.”
Safadi, R., Konikoff, F. M., Mahamid, M., Zelber‐Sagi, S., Halpern, M., Gilat, T., Oren, R., Safadi, R., Konikoff, F. M., Hershkovitz, A., et al. (2014) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2014.04.038 · Cited by 275 · cited 1×
“Aramachol, a fatty acid-bile acid conjugate, is an SCD1 inhibitor that has been tested in a phase 2 trial (Safadi et al., 2014).”
Santoro, N., Zhang, C. K., Zhao, H., PAKSTIS, A. J., Kim, G., Kursawe, R., Dykas, D. J., Bale, A. E., Giannini, C., Pierpont, B. M., et al. (2011) · Hepatology · doi:10.1002/hep.24806 · Cited by 272 · cited 1×
“Less common and more subtle genetic causes have also been identified in pathways that regulate glucose metabolism (e.g., rs1260326 in glucokinase regulatory protein; Santoro et al., 2012).”
A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease
Fernández‐Miranda, C., Pérez-Carreras, M., Colina, F., López-Alonso, G., Vargas, C., & Solis-Herruzo, J. A. (2008) · Digestive and Liver Disease · doi:10.1016/j.dld.2007.10.002 · Cited by 262
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance
Petersen, M. C., Madiraju, A. K., Gassaway, B. M., Marcel, M., Nasiri, A. R., Butrico, G. M., Marcucci, M., Zhang, D., Abulizi, A., Zhang, X., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86013 · Cited by 260
Self-citationThe Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis
Herman, M. A., & Samuel, V. T. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.005 · Cited by 259 · cited 12×
“Fructose is metabolized almost exclusively by the liver, and therefore ingested fructose is funneled into the liver and mostly metabolized to triglycerides by DNL (Herman and Samuel, 2016).”
InfluentialSelf-citationMechanisms of Early Insulin-Sensitizing Effects of Thiazolidinediones in Type 2 Diabetes
Tonelli, J., Li, W., Kishore, P., Pajvani, U. B., Kwon, E., Weaver, C. L., Scherer, P. E., & Hawkins, M. A. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1621 · Cited by 247 · cited 1×
“TZDs decrease ectopic lipid accumulation (Mayerson et al., 2002), decrease visceral adipose tissue mass (Miyazaki et al., 2002; Mori et al., 1999), and improve hepatic and muscle insulin resistance (Mayerson et al., 2002; Petersen et al., 2000; Tonelli et al., 2004).”
Chen, W., Chang, B. H., Li, L., & Chan, L. (2010) · Hepatology · doi:10.1002/hep.23812 · Cited by 246 · cited 1×
“Genetic deletion of this enzyme failed to induce NAFLD in mice (Basantani et al., 2011; Chen et al., 2010), while a PNPLA3 ASO decreased hepatic fatty acid esterification and protected fat-fed rats from NAFLD, PKCε activation, and hepatic insulin resistance (Kumashiro et al., 2013).”
Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans.
Petersen, K. F., Laurent, D., Rothman, D. L., Cline, G. W., & Shulman, G. I. (1998) · Journal of Clinical Investigation · doi:10.1172/jci579 · Cited by 243 · cited 2×
“Similar reductions in glucose transport were observed in insulin-resistant, obese individuals (Petersen et al., 1998a); patients with T2D (Cline et al., 1999); and lean, normoglycemic, but insulin-resistant offspring of T2D parents (Perseghin et al., 1996).”
Self-citationHarwood, H. J., Petras, S. F., Shelly, L. D., Zaccaro, L. M., Perry, D. A., Makowski, M. R., Hargrove, D. M., Martin, K. A., Tracey, W. R., Chapman, J. G., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304481200 · Cited by 243 · cited 1×
“Several novel small molecule inhibitors of ACC have been designed (Harwood et al., 2003; Tong and Harwood, 2006).”
Lockie, S. H., Heppner, K. M., Chaudhary, N., Chabenne, J. R., Morgan, D. A., Veyrat‐Durebex, C., Ananthakrishnan, G., Rohner‐Jeanrenaud, F., Drucker, D. J., DiMarchi, R. D., et al. (2012) · Diabetes · doi:10.2337/db11-1556 · Cited by 240
Henderson, S. J., Konkar, A., Hornigold, D. C., Trevaskis, J. L., Jackson, R., Fritsch Fredin, M., Jansson‐Löfmark, R., Naylor, J., Rossi, A., Bednarek, M. A., et al. (2016) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12735 · Cited by 240
Change in Liver Size and Fat Content after Treatment with Optifast® Very Low Calorie Diet
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“Very-low-calorie diets (e.g., Optifast or LighterLife) can 6 Cell Metabolism 27, January 9, 2017 also quickly improve NAFLD in the span of several weeks (Baldry et al., 2017; Lewis et al., 2006), but are not sustainable indefinitely.”
Basantani, M. K., Sitnick, M. T., Cai, L., Brenner, D., Gardner, N. P., Li, J. Z., Schoiswohl, G., Yang, K., Kumari, M., Gross, R. W., et al. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m011205 · Cited by 238 · cited 1×
“Genetic deletion of this enzyme failed to induce NAFLD in mice (Basantani et al., 2011; Chen et al., 2010), while a PNPLA3 ASO decreased hepatic fatty acid esterification and protected fat-fed rats from NAFLD, PKCε activation, and hepatic insulin resistance (Kumashiro et al., 2013).”
Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids
Vatner, D. F., Majumdar, S. K., Kumashiro, N., Petersen, M. C., Rahimi, Y., Gattu, A. K., Bears, M., Camporez, J.-P. G., Cline, G. W., Jurczak, M. J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423952112 · Cited by 235
Self-citationFructose ingestion acutely stimulates circulating FGF21 levels in humans
Dushay, J. R., Toschi, E., Mitten, E. K., Fisher, F. M., Herman, M. A., & Maratos-Flier, E. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2014.09.008 · Cited by 233
Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice
Camporez, J. P., Jornayvaz, F. R., Petersen, M. C., Pesta, D. H., Guigni, B. A., Serr, J., Zhang, D., Kahn, M., Samuel, V. T., Jurczak, M. J., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1191 · Cited by 232 · cited 2×
“The increases in energy expenditure are associatedwith a reduction in hepatic diacylglycerol content, decreased PKCε activation, and improved insulin signaling (Camporez et al., 2013).”
Self-citationPerry, R. J., Kim, T.-H., Zhang, X., Lee, H., Pesta, D. H., Popov, V., Zhang, D., Rahimi, Y., Jurczak, M. J., Cline, G. W., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.004 · Cited by 230
Self-citationLysophospholipid Acyltransferases and Arachidonate Recycling in Human Neutrophils
Gijón, M. A., Riekhof, W. R., Zarini, S., Murphy, R. C., & Voelker, D. R. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806194200 · Cited by 228
Shi, Y., & Cheng, D. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90949.2008 · Cited by 228 · cited 2×
“MGAT3 is active in humans and also has diacylglycerol transferase activity when 2-monoacyglycerol concentrations are low (Shi and Cheng, 2009).”
Smagris, E., Gilyard, S., BasuRay, S., Cohen, J. C., & Hobbs, H. H. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719955 · Cited by 226 · cited 1×
“The protein may regulate cholesterol metabolism (Fan et al., 2016; Smagris et al., 2016) and the incorporation of polyunsaturated fatty acids into hepatic triglyceride (Luukkonen et al., 2017), but the exact mechanism by which this polymorphism leads to NAFLD remains unclear.”
Intrahepatic Diacylglycerol Content Is Associated With Hepatic Insulin Resistance in Obese Subjects
Magkos, F., Su, X., Bradley, D. P., Fabbrini, E., Conte, C., Eagon, J. C., Varela, J. E., Brunt, E. M., Patterson, B. W., & Klein, S. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.03.003 · Cited by 223 · cited 1×
“Magkos et al. also demonstrated that hepatic DAG content (but not hepatic ceramide content) was the best predictor of hepatic insulin resistance in obese humans (Magkos et al., 2012).”
Mortality in the United States, 1900-1950
Gordon, T. (1953) · Public Health Reports (1896-1970) · doi:10.2307/4588443 · Cited by 222
Gray, L. R., Sultana, M. R., Rauckhorst, A. J., Oonthonpan, L., Tompkins, S. C., Sharma, A., Fu, X., Miao, R., Pewa, A. D., Brown, K., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.027 · Cited by 218 · cited 2×
“and mechanistic target of rapamycin complex 2 (mTORC2) (Guertin and Sabatini, 2007), which converge on Akt phosphorylation (Alessi et al.”
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“This pathway complements diacylglycerol synthesis via the glycerol phosphate pathway and is thought to be very active in enterocytes but upregulated in NAFLD in rodents and humans (Hall et al., 2012).”
Gender Difference in Postprandial Lipemia
Couillard, C., Bergeron, N., Prud’homme, D., Bergeron, J., Tremblay, A., Bouchard, C., Mauriège, P., & Després, J. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.10.2448 · Cited by 215 · cited 1×
“Increases in visceral adipose tissue (VAT) have been associated with dyslipidemia (Després et al., 1990), insulin resistance (Couillard et al., 1999), and NAFLD (Kelley et al., 2003).”
Trends in utilization of bariatric surgery, 2010-2014: sleeve gastrectomy dominates
Khorgami, Z., Shoar, S., Andalib, A., Aminian, A., Brethauer, S. A., & Schauer, P. R. (2017) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2017.01.031 · Cited by 215 · cited 4×
“For the first time, life expectancy in the United States has decreased, and can be partly attributed to obesity-related ‘‘metabolic diseases,’’ including type 2 diabetes (T2D), kidney disease, stroke, and heart disease (Xu et al., 2016).”
InfluentialFibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis
Bhatnagar, S., Damron, H. A., & Hillgartner, F. B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808818200 · Cited by 212 · cited 1×
“But FGF15/19 has additional effects in the liver, such as potentiating glycogen synthesis (Kir et al., 2011) and decreasing expression of gluconeogenic (Potthoff et al., 2011) and lipogenic enzymes (Bhatnagar et al., 2009).”
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“PNPLA3 has dual functions as a triacylglycerol hydrolase and as an acylglycerol transacylase (Kumari et al., 2012), but the mechanism by which this polymorphism—which attenuates the hydrolase activity (Pingitore et al., 2014)—increases liver fat is still unclear.”
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“, 2015) or MPC2 (McCommis et al., 2015) did not alter glucose production on a C57BL/6 background where the block in MPC was bypassed with flux into the mitochondria as alanine and mitochondrial alanine transaminase.”
InfluentialFabbrini, E., Tamboli, R. A., Magkos, F., Marks–Shulman, P. A., Eckhauser, A. W., Richards, W. O., Klein, S., & Abumrad, N. N. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.04.056 · Cited by 207
Acetyl-coenzyme A carboxylases: versatile targets for drug discovery
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“Several novel small molecule inhibitors of ACC have been designed (Harwood et al., 2003; Tong and Harwood, 2006).”
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“In a group of weight-stable patients followed over 10 years, an increase in VAT mass (reflecting ectopic lipid accumulation) was associated with the development of a metabolically unhealthy phenotype (Hwang et al., 2015).”
Francois, M. E., Baldi, J. C., Manning, P. J., Lucas, S. J. E., Hawley, J. A., Williams, M. J. A., & Cotter, J. D. (2014) · Diabetologia · doi:10.1007/s00125-014-3244-6 · Cited by 204 · cited 2×
“Sleeve gastrectomy has recently surpassed RYGB as the most common bariatric procedure performed in the United States (Khorgami et al., 2017) and can resolve steatosis, inflammation, and fibrosis (Billeter et al., 2016; Froylich et al., 2016).”
Nagai, Y., Yonemitsu, S., Erion, D. M., Iwasaki, T., Stark, R., Weismann, D., Dong, J., Zhang, D., Jurczak, M. J., Löffler, M. G., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.011 · Cited by 203 · cited 1×
“For example, monosaccharides also recruit other transcription factors, including ChREBP (Erion et al., 2013; Uyeda and Repa, 2006), PPARg coactivator 1-b (Nagai et al., 2009), and liver X receptor (Bindesbøll et al., 2015), to activate lipogenesis.”
Self-citationNagashima, K., Lopez, C., Donovan, D., Ngai, C., Fontanez, N., Bensadoun, A., Fruchart-Najib, J., Holleran, S., Cohn, J. S., Ramakrishnan, R., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200523219 · Cited by 201 · cited 1×
“TZDs decrease adipocyte inflammation and increase secretion of adiponectin, enhance clearance of VLDL triglyceride (Nagashima et al., 2005), improve insulin-mediated suppression of lipolysis (Mayerson et al., 2002), and lower rates of post-prandial fatty acid turnover (Miles et al., 2003).”
Rabøl, R., Petersen, K. F., Dufour, S., Flannery, C. A., & Shulman, G. I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110105108 · Cited by 195 · cited 2×
“A single bout of elliptical training increased postprandial muscle glycogen synthesis and reduced hepatic DNL without altering plasma insulin concentrations in healthy, young, lean individuals with muscle insulin resistance, emphasizing the importance of altered substrate flux in driving hepatic DNL and NAFLD (Rabøl e…”
Self-citationLeptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis
Perry, R. J., Zhang, X., Zhang, D., Kumashiro, N., Camporez, J. P., Cline, G. W., Rothman, D. L., & Shulman, G. I. (2014) · Nature Medicine · doi:10.1038/nm.3579 · Cited by 193
Self-citationFabbrini, E., Mohammed, B. S., Korenblat, K. M., Magkos, F., McCrea, J., Patterson, B. W., & Klein, S. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2622 · Cited by 192 · cited 2×
“Removal of visceral adipose tissue alone (Fabbrini et al., 2010b) or in conjunction with bariatric surgery does not significantly impact keymetabolic parameters (Andersson et al., 2017; Fabbrini et al., 2010b).”
Finan, B., Clemmensen, C., Zhu, Z., Stemmer, K., Gauthier, K., Müller, L., De Angelis, M., Moreth, K., Neff, F., Perez-Tilve, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.014 · Cited by 191
Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19
Zhou, M., Wang, X., Phung, V., Lindhout, D. A., Mondal, K., Hsu, J.-Y., Yang, H., Humphrey, M., Ding, X., Arora, T., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0208 · Cited by 183
Long-term Metabolic Effects of Laparoscopic Sleeve Gastrectomy
Golomb, I., David, M. M. B., Glass, A., Kolitz, T., & Keidar, A. (2015) · JAMA Surgery · doi:10.1001/jamasurg.2015.2202 · Cited by 181 · cited 1×
“A retrospective analysis of a larger cohort of patients undergoing sleeve gastrectomy found weight regain at 3 and 5 years after surgery and relapse of diabetes in a significant number of patients (e.g., 50% in complete remission at 1 year versus 20% at 5 years; Golomb et al., 2015).”
Sindelar, D., Chu, C. A., Rohlie, M., Neal, D., Swift, L., & Cherrington, A. (1997) · Diabetes · doi:10.2337/diab.46.2.187 · Cited by 179
Luukkonen, P. K., Zhou, Y., Hyötyläinen, T., Leivonen, M., Arola, J. T., Orho‐Melander, M., Orešič, M., & Yki‐Järvinen, H. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.07.045 · Cited by 178
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“…1-triple tetradecylthioacetic acid (TTA, a novel fatty acid analog; Lindquist et al., 2017), and glucoraphanin (a compound present in cruciferous vegetables that promotes browning ofWAT, increases energy expenditure, and protects rodents from diet-induced insulin resistance; Nagata et al., 2017).”
Imamura, M., Takahashi, A., Yamauchi, T., Hara, K., Yasuda, K., Grarup, N., Zhao, W., Wang, X., Huerta‐Chagoya, A., Hu, C., et al. (2016) · Nature Communications · doi:10.1038/ncomms10531 · Cited by 176
Flannery, C. A., Dufour, S., Rabøl, R., Shulman, G. I., & Petersen, K. F. (2012) · Diabetes · doi:10.2337/db12-0206 · Cited by 175 · cited 1×
“Even short (6 min) bursts of exercise before meals can significantly improve the diurnal glucose excursion (Francois et al., 2014).”
Self-citationMinireview: Challenges and Opportunities in Development of PPAR Agonists
Wright, M. B., Bortolini, M., Tadayyon, M., & Bopst, M. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1427 · Cited by 172
Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2
Jornayvaz, F. R., Birkenfeld, A. L., Jurczak, M. J., Kanda, S., Guigni, B. A., Jiang, D. C., Zhang, D., Lee, H., Samuel, V. T., & Shulman, G. I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103451108 · Cited by 169 · cited 2×
“10 Cell Metabolism 27, January 9, 2017 with hepatic insulin resistance (Jornayvaz et al., 2011).”
InfluentialSelf-citationThe liver diseases of lipodystrophy: The long-term effect of leptin treatment
Zadeh, E. S., Lungu, A. O., Cochran, E. K., Brown, R. J., Ghany, M. G., Heller, T., Kleiner, D. E., & Görden, P. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.02.007 · Cited by 169 · cited 1×
“Severe NAFLD/NASH is a complication of congenital lipodystrophies (Safar Zadeh et al., 2013), in which the absence of adipose tissue forces the liver to store excess fatty acids, leading to severe insulin resistance (Kim et al., 2000; Petersen et al., 2002).”
ter Horst, K. W., Gilijamse, P. W., Versteeg, R. I., Ackermans, M. T., Nederveen, A. J., la Fleur, S. E., Romijn, J. A., Nieuwdorp, M., Zhang, D., Samuel, V. T., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.035 · Cited by 166 · cited 1×
“And most recently, Ter Horst et al. have also shown that cytosolic diacylglycerol content and increased PKCε activity are related to hepatic insulin sensitivity in obese individuals undergoing bariatric surgery (Ter Horst et al., 2017).”
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“However, this phenotype was attributed to altered skin integrity and increased energy expenditure (Sampath et al., 2009).”
Metabolism of adipose tissue in intraabdominal depots in severely obese men and women
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“Lipolytic rates in visceral adipose tissue increase in obesity (Nielsen et al., 2004; Rebuffé-Scrive et al., 1990) and may be driven by IL-6 (Wueest et al., 2016).”
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Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms
Rusu, V., Hoch, E., Mercader, J. M., Tenen, D. E., Gymrek, M., Hartigan, C. R., DeRan, M., von Grotthuss, M., Fontanillas, P., Spooner, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.011 · Cited by 152 · cited 1×
“…that decrease expression of the monocarboxylate transporter SCL16A11 have been linked with T2D in Mexicans and Latin Americans (Williams et al., 2014), and in vitro, inhibition of SCL16A11 in hepatocytes promotes accumulation of lipid metabolites, including diacylglycerol (Rusu et al., 2017).”
Non-alcoholic fatty liver disease and risk of type 2 diabetes
Lallukka, S., & Yki‐Järvinen, H. (2016) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2016.06.006 · Cited by 146
Direct effect of GLP-1 infusion on endogenous glucose production in humans
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“GLP1 analogs may also act to decrease hepatic glucose production (Seghieri et al., 2013) and possibly decrease hepatic DNL (Armstrong et al., 2016).”
McCommis, K. S., Hodges, W. T., Brunt, E. M., Nalbantoglu, I., McDonald, W. G., Holley, C. L., Fujiwara, H., Schaffer, J. E., Colca, J. R., & Finck, B. N. (2016) · Hepatology · doi:10.1002/hep.29025 · Cited by 139
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“2016), and protein-protein interaction (MIG-12-mediated polymerization of ACC enhances activity) (Kim et al., 2010).”
Mechanism of troglitazone action in type 2 diabetes.
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“TZDs decrease ectopic lipid accumulation (Mayerson et al., 2002), decrease visceral adipose tissue mass (Miyazaki et al., 2002; Mori et al., 1999), and improve hepatic and muscle insulin resistance (Mayerson et al., 2002; Petersen et al., 2000; Tonelli et al., 2004).”
Self-citationCarino, A., Cipriani, S., Marchianò, S., Biagioli, M., Santorelli, C., Donini, A., Zampella, A., Monti, M. C., & Fiorucci, S. (2017) · Scientific Reports · doi:10.1038/srep42801 · Cited by 135 · cited 2×
“As a significant number of patients experienced pruritus as a side effect, newer non-bile acid FXR agonists have been developed, such as BAR502 (Carino et al., 2017).”
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“However, many now consider VAT as another ectopic site for lipids when subcutaneous adipose tissue capacity is exceeded (Cuthbertson et al., 2017; Jensen, 2008; Smith, 2015).”
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“This polymorphism is also associated with fibrosis in alcoholic liver disease (Buch et al., 2015) and chronic hepatitis C (Thabet et al., 2016), suggesting that this pathway could contain therapeutic targets for several liver diseases.”
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Pioglitazone and Risk for Bone Fracture: Safety Data from a Randomized Clinical Trial
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“In fat-fed rats, the increase in hepatic DAG content activates PKCε, the primary PKC isoform in liver, and also a novel PKC, like PKCq (Qu et al., 1999; Samuel et al., 2004).”
InfluentialChen, Z., Vigueira, P. A., Chambers, K. T., Hall, A. M., Mitra, M. S., Qi, N., McDonald, W. G., Colca, J. R., Kletzien, R. F., & Finck, B. N. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.363960 · Cited by 121 · cited 1×
“One of these compounds, MSDC-0602, improved insulin sensitivity in obese mice, with improvements in hepatic, adipose, and muscle insulin signaling and action (Chen et al., 2012).”
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Self-citation
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Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
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BackgroundInfluentialSelf-citationRole of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease
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The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments
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Mitochondria as a therapeutic target for common pathologies
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Metadata
- Authors
- Samuel, V. T., & Shulman, G. I.
- Affiliations
- United States Department of Veterans Affairs (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Samuel, Varman T.
- Shulman, Gerald I.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 27
- Issue
- 1
- Pages
- 22-41
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5762395
- OpenAlex
- W2752428556
- Cited by
- 745
- References
- 263
- Citations by year
- 2026: 72 · 2025: 84 · 2024: 90 · 2023: 109 · 2022: 88 · 2021: 91 · 2020: 81 · 2019: 71 · 2018: 50
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Celgene
- Novo Nordisk
- National Institutes of Health (DK-40936, DK-45735, DK-R01 DK 11398401)
- AstraZeneca
- Gilead Sciences
- Merck
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- non-alcoholic fatty liver disease, hepatic insulin resistance, diacylglycerol, protein kinase C epsilon, insulin receptor, glycogen synthesis, lipogenesis, gluconeogenesis, pyruvate carboxylase, bariatric surgery, weight loss, PPAR agonists, farnesoid X receptor, FGF21, glucagon-like peptide-1, acetyl-CoA carboxylase, stearoyl-CoA desaturase, mitochondrial uncoupling, therapeutic target
- MeSH terms
- Animals, Glucose, Humans, Insulin, Insulin Resistance, Metabolic Diseases, Lipid Metabolism, Non-alcoholic Fatty Liver Disease
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