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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In concurrent diabetes and insulin resistance, oxidative stress in other tissues due to hyperglycaemia may compound lipotoxicity in the liver.
“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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“Leptin therapy reduced calorie intake, resolved hepatic steatosis, and improved hepatic insulin action (Petersen et al., 2002).”
InfluentialSelf-citationCirculating 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× · see citing works
“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).”
Lotta, 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 587 · see citing works
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
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“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× · see citing works
“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 · see citing works
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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× · see citing works
“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 498 · see citing works
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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 489 · cited 1× · see citing works
“…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 477 · cited 22× · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Savage, D. B. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27300 · Cited by 447 · cited 15× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“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.”
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× · see citing works
“, 2011) and decreasing expression of gluconeogenic (Potthoff et al., 2011) and lipogenic enzymes (Bhatnagar et al.”
Miyazaki, 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 430 · see citing works
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× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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 418 · cited 1× · see citing works
“Some have implicated a specific increase in sugar consumption (Bray and Popkin, 2014).”
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 · see citing works
Self-citationStaels, 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× · see citing works
“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× · see citing works
“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 394 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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 361 · cited 1× · see citing works
“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× · see citing works
“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× · see citing works
“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× · see citing works
“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 337 · cited 1× · see citing works
“Indeed, KB-2115 has been shown to be very efficacious in treating hyperlipidemia (Ladenson et al., 2010).”
Younossi, Z., & Henry, L. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.03.005 · Cited by 334 · cited 1× · see citing works
“However, nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as the most common chronic liver disease (Younossi and Henry, 2016).”
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 324 · cited 1× · see citing works
“Specific changes in adipose tissue gene expression have also been associated with the development of NASH (du Plessis et al., 2015).”
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× · see citing works
“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× · see citing works
“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).”
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 313 · cited 1× · see citing works
“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).”
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× · see citing works
“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).”
Abdominal obesity: a marker of ectopic fat accumulation
Smith, U. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81507 · Cited by 299 · cited 1× · see citing works
“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).”
Juárez, R. G. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26991 · Cited by 298 · see citing works
Mao, J., DeMayo, F. J., Huiguang, L., Abu-Elheiga, L. A., Gu, Z., Shaiken, 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 292 · cited 2× · see citing works
“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.”
Zhang, S., Wang, J., Liu, Q., & Harnish, D. C. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.025 · Cited by 290 · see citing works
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 288 · cited 1× · see citing works
“However, actual histological improvements in inflammation and fibrosis were not evident (Klein et al., 2006).”
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 · see citing works
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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…”
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× · see citing works
“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).”
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 286 · see citing works
Self-citationControlled-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 · see citing works
Effect 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× · see citing works
“, 2002), decrease visceral adipose tissue mass (Miyazaki et al., 2002; Mori et al., 1999), and improve hepatic and muscle insulin resistance (Mayerson et al.”
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 280 · cited 1× · see citing works
“These results have been replicated by other hypocaloric feeding studies (Lazo et al., 2010; Lim et al., 2011).”
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× · see citing works
“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 263 · cited 1× · see citing works
“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 255 · see citing works
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 255 · cited 2× · see citing works
“SCD1 ASO therapy protected mice against NAFLD on a high-fat diet with several changes associated with increased energy expenditure (Jiang et al., 2005).”
Mechanisms 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 249 · cited 1× · see citing works
“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).”
The 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 249 · cited 12× · see citing works
“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-citationChen, W., Chang, B. H., Li, L., & Chan, L. (2010) · Hepatology · doi:10.1002/hep.23812 · Cited by 246 · cited 1× · see citing works
“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).”
Change in Liver Size and Fat Content after Treatment with Optifast® Very Low Calorie Diet
Lewis, M. C., Phillips, M. L., Slavotinek, J., Kow, L., Thompson, C., & Toouli, J. (2006) · Obesity Surgery · doi:10.1381/096089206777346682 · Cited by 242 · cited 1× · see citing works
“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.”
Harwood, 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 242 · cited 1× · see citing works
“Several novel small molecule inhibitors of ACC have been designed (Harwood et al., 2003; Tong and Harwood, 2006).”
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 242 · see citing works
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“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).”
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/jci200523962 · Cited by 239 · see citing works
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 238 · see citing works
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 237 · cited 2× · see citing works
“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-citationInsulin-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 · see citing works
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 · see citing works
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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 · see citing works
Shi, Y., & Cheng, D. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90949.2008 · Cited by 228 · cited 2× · see citing works
“MGAT3 is active in humans and also has diacylglycerol transferase activity when 2-monoacyglycerol concentrations are low (Shi and Cheng, 2009).”
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 226 · cited 2× · see citing works
“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-citationSmagris, 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× · see citing works
“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× · see citing works
“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 · see citing works
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“and mechanistic target of rapamycin complex 2 (mTORC2) (Guertin and Sabatini, 2007), which converge on Akt phosphorylation (Alessi et al.”
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Gender Difference in Postprandial Lipemia
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“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).”
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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.”
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 211 · cited 4× · see citing works
“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).”
InfluentialMcCommis, K. S., Chen, Z., Fu, X., McDonald, W. G., Colca, J. R., Kletzien, R. F., Burgess, S. C., & Finck, B. N. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.07.028 · Cited by 210 · cited 3× · see citing works
“, 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.”
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 209 · cited 1× · see citing works
“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).”
Haas, J. T., Miao, J., Chanda, D., Wang, Y., Zhao, E., Haas, M. E., Hirschey, M. D., Vaitheesvaran, B., Farese, R. V., Kurland, I. J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.002 · Cited by 207 · cited 1× · see citing works
“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).”
Fabbrini, 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 · see citing works
Acetyl-coenzyme A carboxylases: versatile targets for drug discovery
Tong, L., & Harwood, H. J. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21077 · Cited by 207 · cited 1× · see citing works
“Several novel small molecule inhibitors of ACC have been designed (Harwood et al., 2003; Tong and Harwood, 2006).”
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× · see citing works
“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).”
Hwang, Y.-C., Hayashi, T., Fujimoto, W. Y., Kahn, S. E., Leonetti, D. L., McNeely, M. J., & Boyko, E. J. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.75 · Cited by 203 · cited 1× · see citing works
“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).”
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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“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 · see citing works
Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19
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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 178 · cited 1× · see citing works
“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).”
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 · see citing works
Nagata, N., Xu, L., Kohno, S., Ushida, Y., Aoki, Y., Umeda, R., Fuke, N., Zhuge, F., Ni, Y., Nagashimada, M., et al. (2017) · Diabetes · doi:10.2337/db16-0662 · Cited by 178 · cited 1× · see citing works
“…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 174 · see citing works
Minireview: 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 169 · see citing works
Flannery, C. A., Dufour, S., Rabøl, R., Shulman, G. I., & Petersen, K. F. (2012) · Diabetes · doi:10.2337/db12-0206 · Cited by 169 · cited 1× · see citing works
“Even short (6 min) bursts of exercise before meals can significantly improve the diurnal glucose excursion (Francois et al., 2014).”
Self-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 166 · cited 1× · see citing works
“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× · see citing works
“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).”
Self-citationHepatic 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 164 · cited 2× · see citing works
“10 Cell Metabolism 27, January 9, 2017 with hepatic insulin resistance (Jornayvaz et al., 2011).”
InfluentialSelf-citationSampath, H., Flowers, M. T., Liu, X., Paton, C. M., Sullivan, R., Chu, K., Zhao, M., & Ntambi, J. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.014225 · Cited by 164 · cited 1× · see citing works
“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
Rebuffé-Scrive, M., Anderson, B. M., Olbe, L. C., & Björntorp, P. A. (1990) · Metabolism · doi:10.1016/0026-0495(90)90160-e · Cited by 159 · cited 1× · see citing works
“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).”
Cao, J., Zhou, Y., Peng, H., Huang, X., Stahler, S. L., Suri, V., Qadri, A., Gareski, T., Jones, J. E., Hahm, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.245456 · Cited by 154 · see citing works
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× · see citing works
“…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).”
Direct effect of GLP-1 infusion on endogenous glucose production in humans
Seghieri, M., Rebelos, E., Gastaldelli, A., Astiarraga, B. D., Casolaro, A., Barsotti, E., Pocai, A., Nauck, M., Muscelli, E., & Ferrannini, E. (2013) · Diabetologia · doi:10.1007/s00125-012-2738-3 · Cited by 143 · cited 1× · see citing works
“GLP1 analogs may also act to decrease hepatic glucose production (Seghieri et al., 2013) and possibly decrease hepatic DNL (Armstrong et al., 2016).”
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 138 · see citing works
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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.
Petersen, K. F., Krššák, M., Inzucchi, S. E., Cline, G. W., Dufour, S., & Shulman, G. I. (2000) · Diabetes · doi:10.2337/diabetes.49.5.827 · Cited by 136 · cited 1× · see citing works
“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 132 · cited 2× · see citing works
“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).”
Thabet, K., Asimakopoulos, A., Shojaei, M., Romero‐Gómez, M., Mangia, A., Irving, W. L., Berg, T., Dore, G. J., Grønbæk, H., Sheridan, D. A., et al. (2016) · Nature Communications · doi:10.1038/ncomms12757 · Cited by 130 · cited 1× · see citing works
“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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“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-citation13C/31P NMR studies on the mechanism of insulin resistance in obesity.
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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 · see citing works
“Othermetabolic causes of NAFLD andNASH, which are most often genetically related, include (1) defects in intrahepatic lipolysis (e.g., decreased ATGL/CGI-58 activity); (2) defects in triglyceride export (e.g., defective Apo-B 100, MTTP activity); (3) increased glucokinase activity, resulting in increased hepatic DNL;…”
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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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“In fat metabolism, the liver cells break down fats and produce energy (reviewed in [162]).”
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AMP-activated protein kinase: the current landscape for drug development
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Metabolic-associated fatty liver disease and lipoprotein metabolism
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Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity
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Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus
Ferguson, D., & Finck, B. N. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00507-z · Cited by 507 · see citing works
The cell biology of systemic insulin function
Tokarz, V. L., MacDonald, P. E., & Klip, A. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201802095 · Cited by 471 · see citing works
“This ensures that a portion of dietary glucose is effectively stored in the liver and is only released to the rest of the body upon cessation of insulin action (between meals) or upon metabolic demand enacted by other “counterregulatory” hormones (Samuel and Shulman, 2018).”
BackgroundMantovani, A., Petracca, G., Beatrice, G., Csermely, A., Lonardo, A., Schattenberg, J. M., Tilg, H., Byrne, C. D., & Targher, G. (2022) · Gut · doi:10.1136/gutjnl-2020-323082 · Cited by 402 · see citing works
Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo
Feyter, H. M. D., Behar, K. L., Corbin, Z. A., Fulbright, R. K., Brown, P. B., McIntyre, S., Nixon, T. W., Rothman, D. L., & de Graaf, R. A. (2018) · Science Advances · doi:10.1126/sciadv.aat7314 · Cited by 378 · see citing works
“(D) 2H NMR spectra from selected locations depicted in the T2W MR image, including tissue (1 and 3) within the lesion as seen on T1W CE, (2) from normal-appearing occipital lobe, and (4) containing cerebrospinal fluid from the left lateral ventricle.”
BackgroundXu, X., Poulsen, K. L., Wu, L., Liu, S., Miyata, T., Song, Q., Wei, Q., Zhao, C., Lin, C., & Yang, J. B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01119-3 · Cited by 370 · see citing works
“of a profibrotic environment appear to be promising therapeutic strategies.(71,72) Here we review some of the most promising therapeutic targets for NASH, and describe compounds being evaluated against these targets in clinical or preclinical stages (Tables 1 and 2).”
BackgroundWhite, P. J., McGarrah, R. W., Grimsrud, P. A., Tso, S.-C., Yang, W.-H., Haldeman, J. M., Grenier-Larouche, T., An, J., Lapworth, A. L., Astapova, I., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.015 · Cited by 365 · see citing works
“We also observed improved glucose tolerance in response to those maneuvers, possibly secondary to the marked lowering of hepatic TG content (Samuel and Shulman, 2017).”
Rao, Y., Kuang, Z., Li, C., Guo, S., Xu, Y., Zhao, D., Hu, Y., Song, B., Jiang, Z., Ge, Z., et al. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1927633 · Cited by 356 · see citing works
“Diacylglycerol (DAG) is a representative intermediate of lipid metabolism that induces activation of oxidative stress and displays toxicity to hepatocytes, leading to apoptosis and liver injury in vivo.(26) Notably, treatment with A.”
BackgroundAn integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH
Tacke, F., Puengel, T., Loomba, R., & Friedman, S. L. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.03.038 · Cited by 321 · see citing works
Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
Francque, S., Szabo, G., Abdelmalek, M. F., Byrne, C. D., Cusi, K., Dufour, J.-F., Roden, M., Sacks, F., & Tacke, F. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00366-5 · Cited by 316 · see citing works
Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD
Garcia, D., Hellberg, K., Chaix, A., Wallace, M., Herzig, S., Badur, M. G., Lin, T. C., Shokhirev, M. N., Pinto, A. F. M., Ross, D. S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.036 · Cited by 294 · see citing works
“In the liver, PKCε is the isoform most strongly associated with lipid-induced hepatic insulin resistance (Samuel and Shulman, 2018).”
BackgroundInfluentialPharmacotherapy for NASH: Current and emerging
Konerman, M. A., Jones, J. C., & Harrison, S. A. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.10.015 · Cited by 293 · see citing works
“Journal of storage via stimulation of lipogenesis and inhibition of lipid oxidation.(63) Mouse models of ACC inhibitors have shown that these agents can reduce liver triglycerides, but were also noted to increase plasma triglycerides.”
Metabolic and Signaling Roles of Ketone Bodies in Health and Disease
Puchalska, P., & Crawford, P. A. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-111120-111518 · Cited by 290 · see citing works
Dietary carbohydrates and fats in nonalcoholic fatty liver disease
Yki-Järvinen, H., Luukkonen, P. K., Hodson, L., & Moore, J. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00472-y · Cited by 294 · see citing works
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“A growing evidence supports the same pathogenesis in the development and progression of T2DM and NAFLD, including hyperglycemia, oxidative stress, cellular inflammatory factors, and insulin resistance (Gao & Tsukamoto, 2016; Haas, Francque, & Staels, 2016; Samuel & Shulman, 2018).”
BackgroundLuukkonen, P. K., Dufour, S., Lyu, K., Zhang, X., Hakkarainen, A., Lehtimäki, T. E., Cline, G. W., Petersen, K. F., Shulman, G. I., & Yki‐Järvinen, H. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922344117 · Cited by 253 · see citing works
“The marked fall in IHTG is also likely to underrepresent a considerable fall in intrahepatocellular diacylglycerol content, a key mediator of hepatic insulin resistance (1, 45), under conditions of reduced net re-esterification.”
BackgroundSelf-citationDela Cruz, C. S., & Kang, M.-J. (2018) · Mitochondrion · doi:10.1016/j.mito.2017.12.001 · Cited by 255 · see citing works
“Although the underlying pathophysiologic mechanism that contribute to the development and progression of NAFLD and NASH are complex (Samuel and Shulman, 2017), the activation of the innate immune system in association with chronic inflammation has been highlighted as an important feature of its pathogenesis (Arrese et…”
The circadian clock and liver function in health and disease
Mukherji, A., Bailey, S. M., Staels, B., & Baumert, T. F. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.03.020 · Cited by 246 · see citing works
“generally initiated by perturbations in free fatty acid (FFA) metabolism, which drives excessive TG accumulation in hepatocytes ((36-37)).”
BackgroundInfluentialmiRNAs and NAFLD: from pathophysiology to therapy
Gjorgjieva, M., Sobolewski, C., Dolicka, D., de Sousa, M. C., & Foti, M. (2019) · Gut · doi:10.1136/gutjnl-2018-318146 · Cited by 242 · see citing works
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Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies
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Intestinal Barrier and Permeability in Health, Obesity and NAFLD
Portincasa, P., Bonfrate, L., Khalil, M., Angelis, M. D., Calabrese, F. M., D’Amato, M., Wang, D. Q. ‐., & Ciaula, A. D. (2021) · Biomedicines · doi:10.3390/biomedicines10010083 · Cited by 212 · see citing works
“According to a recent debate, the term “non-alcoholic” seems to overemphasize “alcohol” rather than metabolic risk factors [306,346].”
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“Therefore, one approach to treat NAFLD is to reduce the endogenous production of fatty acids in the liver by inhibiting de novo lipogenesis [48, 49].”
BackgroundInhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia
Morrow, M. R., Batchuluun, B., Wu, J., Ahmadi, E., Leroux, J. M., Mohammadi-Shemirani, P., Desjardins, E. M., Wang, Z., Tsakiridis, E. E., Lavoie, D. C. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.05.004 · Cited by 199 · see citing works
Vitamin D and Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): An Update
Barchetta, I., Cimini, F. A., & Cavallo, M. G. (2020) · Nutrients · doi:10.3390/nu12113302 · Cited by 188 · see citing works
“As a vicious circle, once MAFLD is established it increases the hepatic insulin resistance, which, in turn, may trigger, in 30–40% of cases, MAFLD evolution towards steatohepatitis (NASH), and eventually, cirrhosis, liver failure, and hepatocarcinoma [4,5].”
BackgroundLuci, C., Bourinet, M., Leclère, P. S., Anty, R., & Gual, P. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.597648 · Cited by 195 · see citing works
“Weight gain, insulin resistance, type 2 diabetes mellitus, and hypertension are risk factors for NAFLD progression (6, 7).”
BackgroundA Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu, K., Zhang, Y., Zhang, D., Kahn, M., ter Horst, K. W., Rodrigues, M. R. D. S., Gaspar, R. C., Hirabara, S. M., Luukkonen, P. K., Lee, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.001 · Cited by 173 · see citing works
“DAGs, the penultimate intermediate in triglyceride synthesis, have been shown to be highly associated with hepatic steatosis and HIR in both rodents and humans (Abulizi et al., 2017; Kumashiro et al., 2011; Luukkonen et al., 2016; Magkos et al., 2012; Perry et al., 2015b; Samuel and Shulman, 2018; Ter Horst et al., 20…”
BackgroundSelf-citationInsights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases
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“Ingested glucose is re-directed to the liver during insulin resistant status [47] and glucose is primarily processed to FA via DNL [46,52].”
BackgroundAlkhouri, N., Lawitz, E., Noureddin, M., DeFronzo, R., & Shulman, G. I. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1668374 · Cited by 162 · see citing works
“potent anti-steatotic action and beneficial effects on lipids and cardiovascular outcomes may prove to be more efficacious than GS-0976 [23].”
BackgroundSelf-citationMitogen-Activated Protein Kinase Regulation in Hepatic Metabolism
Lawan, A., & Bennett, A. M. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.10.007 · Cited by 162 · see citing works
Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis
Zhao, X.-Y., Xiong, X., Liu, T., Mi, L., Peng, X., Rui, C., Guo, L., Li, S., Li, X., & Lin, J. D. (2018) · Nature Communications · doi:10.1038/s41467-018-05383-2 · Cited by 162 · see citing works
Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism
Ardestani, A. D., Lupše, B., & Maedler, K. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.04.006 · Cited by 161 · see citing works
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Self-citationPlasma Free Fatty Acid Concentration as a Modifiable Risk Factor for Metabolic Disease
Henderson, G. C. (2021) · Nutrients · doi:10.3390/nu13082590 · Cited by 152 · see citing works
“Elevated DAG can lead to IR though activation of specific protein kinase C isoforms [28,32,33].”
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“such as cardiovascular complications and certain cancers, leading to a consequent increase in mortality, morbidity, and economic burden [3].”
BackgroundStructural basis for FGF hormone signalling
Chen, L., Fu, L., Sun, J., Huang, Z., Fang, M., Zinkle, A., Liu, X., Lu, J., Pan, Z., Wang, Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06155-9 · Cited by 147 · see citing works
Glucocorticoid-Induced Fatty Liver Disease
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Lipid Metabolism in Metabolic-Associated Steatotic Liver Disease (MASLD)
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Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease
Grossmann, M., Wierman, M. E., Angus, P., & Handelsman, D. J. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00158 · Cited by 144 · see citing works
Endocrine role of bone in the regulation of energy metabolism
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“…individuals with MASLD should be managed by improving the systemic metabolic homeostasis [198], dysregulation of glucose and lipid metabolism [82], and eventually correct the involvement of skeletal muscle (i.e., myosteatosis, sarcopenia, and release of myokines) [199,200], of intestinal…”
BackgroundInfluentialHepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity
Régnier, M., Polizzi, A., Smati, S., Lukowicz, C., Fougerat, A., Lippi, Y., Fouché, E., Lasserre, F., Naylies, C., Bétoulières, C., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-63579-3 · Cited by 141 · see citing works
Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies?
Ciaula, A. D., Passarella, S., Shanmugam, H., Noviello, M., Bonfrate, L., Wang, D. Q. ‐., & Portincasa, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105375 · Cited by 133 · see citing works
“In lipid synthesis, FFA in the hepatocyte cytosol is esterified with glycerol to form TG via the key enzymes, diglyceride acyltransferase (DGAT)1 and DGAT2, and exported to blood as very-low-density lipoprotein (VLDL) [38].”
BackgroundHepatic glucose metabolism in the steatotic liver
Scoditti, E., Sabatini, S., Carli, F., & Gastaldelli, A. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00888-8 · Cited by 134 · see citing works
“Intrahepatic content of DAG — the penultimate intermediate in triglyceride synthesis — is highly correlated with Hep-IR in rats, mice and humans 44,59–61 .”
Helsley, R. N., Varadharajan, V., Brown, A. L., Gromovsky, A. D., Schugar, R. C., Ramachandiran, I., Fung, K., Kabbany, M. N., Banerjee, R., Neumann, C. K. A., et al. (2019) · eLife · doi:10.7554/elife.49882 · Cited by 132 · see citing works
An integrative systems genetic analysis of mammalian lipid metabolism
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Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis
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“For example, diacylglycerol, the penultimate intermediate in the triglyceride synthesis pathways, and ceramide, a complex membrane lipid, have been shown to inhibit insulin signaling at the insulin receptor or proximal mediators (6,7).”
BackgroundEmerging Molecular Targets for Treatment of Nonalcoholic Fatty Liver Disease
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“For example, it has been demonstrated that GLP-1 receptor agonists and SGLT-2 inhibitors, in addition to their ability to lower glucose levels, have the potential to enhance atherogenic dyslipidemia and decrease cardiovascular events in individuals diagnosed with type 2 diabetes [9,10].”
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“(Cell Mol Gastroenterol Hepatol 2021;12:857–871; https://doi.org/ 10.1016/j.jcmgh.2021.05.006) Keywords: Sodium Butyrate; Insulin-Induced Gene; LKB1; Hepatic Lipogenesis; NAFLD. epatic steatosis is a major characteristic of nonal- *Authors share co-first authorship Abbreviations used in this paper: ACC, acetyl-CoA car…”
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“Yet in NASH, mitochondrial adaptations are completely lost, and a low respiration rate and increased mitochondrial mass were observed [11, 12].”
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“In the liver, the metabolism of lipids is regulated by nuclear receptors that activate diverse ligands and modulate important enzymes involved in lipogenesis and lipoxidation [181], acting as redox triggers that in turn affect several metabolic pathways due to particular ROS [182].”
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FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation
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“support that FGF21 independent of weight loss protected the liver against inflammation and inflammatory processes (25, 68-70) An important question is whether the findings in the DIO mice can be translated into humans.”
BackgroundLipophagy: Molecular Mechanisms and Implications in Metabolic Disorders.
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“NAFLD exhibits insulin resistance and lipogenesis (Samuel and Shulman, 2018; Tavernarakis et al., 2019).”
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“…and insulin sensitivity by combined exposure to BPA and arsenic may be due to the upregulation of enzymes or genes involved in gluconeogenesis (Gys2) and glucose uptake (Glut2), as insulin is known to activate glucose transport and gluconeogenesis in skeletal muscle (Samuel and Shulman 2018).”
BackgroundThe Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress
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“These studies did not demonstrate any association between insulin sensitivity and other factors implicated in hepatic insulin resistance, such as ceramide content, endoplasmic reticulum stress markers, or inflammatory cytokine concentrations.60–63 Studies with mice lacking glycogen synthase demonstrate increased lipog…”
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BackgroundInfluentialEffects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans
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- 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 · 2017: 8
- 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 › Epidemiology › 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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