Horm Mol Biol Clin Invest 2014; 20(2): 39–41
Giovanni Tarantino*
Nutrition: a promising route for prevention and management of obesity-related nonalcoholic fatty liver disease Abstract: When dealing with the treatment of obesitylinked illnesses – in particular nonalcoholic fatty liver disease – beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition. Keywords: diet; nonalcoholic fatty liver disease (NAFLD); obesity. DOI 10.1515/hmbci-2014-0034 Received October 27, 2014; accepted October 29, 2014
The rising incidence of obesity in today’s environment is associated with many obesity-related health complications [1], including nonalcoholic fatty liver disease (NAFLD), hypertension and coronary artery disease (CAD), hyperlipidemia and type 2 diabetes (T2D) – with all these diseases clustered in the so-called metabolic syndrome [2]. Most obese patients are characterized by a low-grade chronic inflammation of the adipose tissue, mainly visceral (VAT), resulting from chronic activation of the innate immune system subsequently leading to impaired glucose metabolism, i.e., insulin resistance (IR). *Corresponding author: Giovanni Tarantino, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Italy; and Centro Ricerche Oncologiche di Mercogliano, Istituto Nazionale Per Lo Studio E La Cura Dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Italy, E-mail: [email protected]
Adipose tissue has been more recently recognized as a key player in various processes beyond functioning as the main place devoted to energy storage. In obesity, adipose tissue, partly, but not only due to its expansion, is characterized by an increased production and secretion of a wide range of factors, called cytokine/adipokines. Starting with inflammatory cytokines, they have local but also systemic effects on other organs. To prove this strict link between adipose tissue and inflammation, weight loss is followed by a reduction in the macrophage infiltration of adipose tissue and an improvement of the inflammatory profile of gene expression [3]. It has been repeatedly hypothesized that IR is the basic alteration of obesity-related NAFLD. Although a hepatocyte IR does exist, the precise mechanism of adipocyte IR in obesityrelated NAFLD remains a subject of controversy, but an emerging body of data suggest that an altered adipocytokine milieu in visceral fat resulting from macrophage infiltration is important [4]. But, not only do adipocytes play an important role in infiltrated macrophages but they also contribute per se to the pathogenesis of IR, modulating adipokines release. These intriguing hormones are down-regulated in the expression; for example, adiponectin, thought to be an insulin-sensitising effector, or conversely, over-expressed during obesity, including leptin and resistin. Circulating levels of adiponectin are decreased in subjects with obesity-related IR, type 2 diabetes and CAD. Adiponectin inhibits liver neo-glucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and likely protects against the development of arteriosclerosis [5]. Leptin has the propriety to modulate TNF-alpha production and macrophage activation. We have strong evidence that TNF-alpha is over-expressed in adipose tissue of several animal models of obesity and has an important role in the pathogenesis of IR in these species. IL-6 secretion and release by human adipose tissue increases in obese patients. It leads to hepatic CRP synthesis and is involved in the onset of cardiovascular complications. Both TNFalpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signaling pathway. The
40 Tarantino: Diet and NAFLD pro-inflammatory effects of cytokines, through intracellular signaling pathways, involve the NF-kappaB and JNK systems. Genetic but also pharmacological manipulations of these effectors of the inflammatory response have been thought of as able to ameliorate insulin sensitivity in animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their antiinflammatory properties. In rodents, resistin can induce IR, while its implication in the control of insulin sensitivity is still a matter of debate in humans. It has been suggested that impaired skeletal muscle mitochondrial function may contribute to ectopic lipid deposition, obviously also in the liver, and the associated metabolic syndrome, by altering post-prandial energy storage. Recently, authors provided evidence that skeletal muscle mitochondrial function is preserved in patients with NAFLD, compared with age, BMI and fitness-matched healthy controls, and cannot account for ectopic fat deposition or the high prevalence of metabolic syndrome. This research confirms that factors other than skeletal muscle mitochondrial dysfunction play a role in NAFLD, suggesting that skeletal muscle and adipose tissue IR play a major role [6]. NAFLD is a multifactorial disease that involves a complex interaction of genetics, diet, and lifestyle, all of which combine to form the NAFLD phenotype. NAFLD – or generally speaking hepatic steatosis (HS) – is defined as the accumulation of lipid, primarily in the form of triacylglycerols in individuals who do not consume significant amounts of alcohol ( 30) may show features of hepatic stetosis, called by some authors lean NAFLD or better non-obese-NAFLD. Nevertheless the more severe form of this non-obese NAFLD, i.e., nonalcoholic steatohepatits (NASH) is characterized by a strong criterium of the metabolic syndrome, i.e., hypertension [7]. Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with simple FL and NASH [8], prompting to cure not only the more severe form, but also that once thought the benign form, i.e., FL. As aforementioned, recent data indicate that adipose tissue is the site of infiltrated macrophages, being a major source of locally-produced pro-inflammatory
cytokines, but also acting distantly. Accordingly, many efforts have been made to reduce inflammation and IR. The main mechanism proven to induce HS consists in the augmented process of lipolysis in adipose tissue, mainly in the visceral adipose tissue, which dramatically increases free fatty acid influx directly into the liver by the portal vein. Collaterally, a de novo synthesis of free fatty acids from liver has been ascertained with relative impact on their total amount. The free fatty acids lead to triglyceride synthesis and increased glucose production by altering the suppression of the release of hepatic glucose mediated by insulin. In addition, free fatty acids, ligands of the membrane-bound TLR4, promote per se inflammation [9]. Furthermore, body weight excess, particularly visceral, with its pro-inflammatory status, is strictly associated with NAFLD, even though inflammation is balanced by anti-inflammatory factors secreted by inflamed adipose tissue. Among them, adiponectin plays a key role. Fructose excess is thought to be a possible cause in inducing and worsening NAFLD, even though, on the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (i.e., liver fat, hepatic de novo lipogenesis, ALT/AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD [10]. Bariatric surgery for severely obese patients as well as for those suffering from T2D are considered valid and safe alternative strategies to obtain weight loss and metabolic equilibrium and also the improvement of HS. Drugs have evidenced scarce or null effect in modifying ectopic fat in the liver. Recently, in contrast with the deluding findings of therapeutic approaches, regular aspirin use ( ≥ 15 times per month) may be associated with a lower prevalence of NAFLD, primarily among men and older patients [11]. A cornerstone of the management strategy in such patients with FL is the use of diet to decrease body weight, and improve IR, dyslipidemia and cardiovascular risks. Indeed, the target of reducing the visceral fat (obesity), considered a potential treatment strategy in order to cure NAFLD [12], and prevent or delay age-related diseases and to increase longevity [13], is generally thought to be a difficult one to meet. In fact, our Western society is progressively obese in part due to lack of exercise and increased availability of high-calorie dense food. As correctly emphasized in a recent review published [14], “NAFLD patients, whether obese or not, should be educated that a healthy diet and physical activity have benefits beyond weight reduction”. Although evidence
Tarantino: Diet and NAFLD 41
reiterates the difficulty in achieving success in every-day practice, drawing attention to alternative therapies for weight loss in NAFLD, the link between, a hypocaloric, hypoglicidic, hypolipidemic diet and NAFLD strongly conveys that a balanced nutrition could improve and/ or prevent NAFLD. Obviously, the correct diet of NAFLD patients can be achieved by the development of an appropriate nutrition composition/caloric balance. Among nutrients that play an important role in maintaining the liver metabolism the use of wine in low quantities should be mentioned. The effect of modest alcohol consumption on NAFLD does not seem to be exclusively associated with reduced IR or with the low prevalence of metabolic syndrome features. The liver protective effects of modest wine drinking are linked to reduction of triglyceride content of liver or an increase in circulating adiponectin, suggesting that the prevention of HS is mediated through AMPK and PPRAα. An intriguing mechanisms supports the role of enhanced activation of adiponectin receptor 2 in reducing liver fat. But, various other nutritional ingredients are reported to be useful, such as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all showing promising but not definite results. When dealing with the treatment of obesity-linked illnesses, in particular NAFLD, an emerging field of study is represented by prebiotics/ probiotics and restoration of normal gut flora, which could play a fundamental role in diet and its various components [15]. As a final comment, it is noteworthy to point out that both improving or reducing the severity of NAFLD bears a positive consequence on the evolution of atherosclerosis and its cardiovascular-associated disease, such as CAD, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature [16]. But, who could exclude the role of nutrition in modulating the acquired immunity in this condition?
References 1. Pi-Sunyer FX. The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 2002;10:97S–104S. 2. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol 2007;22:293–303. 3. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumié A,
Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clément K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgeryinduced weight loss. Diabetes 2005;54:2277–86. 4. Deng W, Wang X, Xiao J, Chen K, Zhou H, Shen D, Li H, Tang Q. Loss of regulator of g protein signaling 5 exacerbates obesity, hepatic steatosis, inflammation and insulin resistance. PLoS One 2012;7:e30256. 5. Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013;19:802–12. 6. Cuthbertson DJ, Irwin A, Sprung VS, Jones H, Pugh CJ, Daousi C, Adams VL, Bimson WE, Shojaee-Moradie F, Richardson P, Umpleby AM, Wilding JP, Kemp GJ. Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle. Clin Sci (Lond) 2014;127:655–63. 7. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, Srishord M. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 2012;91:319–27. 8. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of pairedbiopsy studies. Clin Gastroenterol Hepatol 2014;S1542–65. 9. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015–25. 10. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr 2014;100:833–49. 11. Shen H, Shahzad G, Jawairia M, Bostick RM, Mustacchia P. Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. Aliment Pharmacol Ther 2014;40:1066–73. 12. Finelli C, Tarantino G. Have guidelines addressing physical activity been established in nonalcoholic fatty liver disease? World J Gastroenterol 2012;18:6797–807. 13. Finelli C, Sommella L, Gioia S, La Sala N, Tarantino G. Should visceral fat be reduced to increase longevity? Ageing Res Rev 2013;12:996–1004. 14. Nseir W, Hellou E, Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:9338–44. 15. Tarantino G. Gut microbiome, obesity-related comorbidities, and low-grade chronic inflammation. J Clin Endocrinol Metab 2014;99:2343–6. 16. Tarantino G, Costantini S, Finelli C, Capone F, Guerriero E, La Sala N, Gioia S, Castello G. Carotid intima-media thickness is predicted by combined eotaxin levels and severity of hepatic steatosis at ultrasonography in obese patients with nonalcoholic Fatty liver disease. PLoS One 2014;9:105610.
Copyright of Hormone Molecular Biology & Clinical Investigation is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Giovanni Tarantino*
Nutrition: a promising route for prevention and management of obesity-related nonalcoholic fatty liver disease Abstract: When dealing with the treatment of obesitylinked illnesses – in particular nonalcoholic fatty liver disease – beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition. Keywords: diet; nonalcoholic fatty liver disease (NAFLD); obesity. DOI 10.1515/hmbci-2014-0034 Received October 27, 2014; accepted October 29, 2014
The rising incidence of obesity in today’s environment is associated with many obesity-related health complications [1], including nonalcoholic fatty liver disease (NAFLD), hypertension and coronary artery disease (CAD), hyperlipidemia and type 2 diabetes (T2D) – with all these diseases clustered in the so-called metabolic syndrome [2]. Most obese patients are characterized by a low-grade chronic inflammation of the adipose tissue, mainly visceral (VAT), resulting from chronic activation of the innate immune system subsequently leading to impaired glucose metabolism, i.e., insulin resistance (IR). *Corresponding author: Giovanni Tarantino, Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Italy; and Centro Ricerche Oncologiche di Mercogliano, Istituto Nazionale Per Lo Studio E La Cura Dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Italy, E-mail: [email protected]
Adipose tissue has been more recently recognized as a key player in various processes beyond functioning as the main place devoted to energy storage. In obesity, adipose tissue, partly, but not only due to its expansion, is characterized by an increased production and secretion of a wide range of factors, called cytokine/adipokines. Starting with inflammatory cytokines, they have local but also systemic effects on other organs. To prove this strict link between adipose tissue and inflammation, weight loss is followed by a reduction in the macrophage infiltration of adipose tissue and an improvement of the inflammatory profile of gene expression [3]. It has been repeatedly hypothesized that IR is the basic alteration of obesity-related NAFLD. Although a hepatocyte IR does exist, the precise mechanism of adipocyte IR in obesityrelated NAFLD remains a subject of controversy, but an emerging body of data suggest that an altered adipocytokine milieu in visceral fat resulting from macrophage infiltration is important [4]. But, not only do adipocytes play an important role in infiltrated macrophages but they also contribute per se to the pathogenesis of IR, modulating adipokines release. These intriguing hormones are down-regulated in the expression; for example, adiponectin, thought to be an insulin-sensitising effector, or conversely, over-expressed during obesity, including leptin and resistin. Circulating levels of adiponectin are decreased in subjects with obesity-related IR, type 2 diabetes and CAD. Adiponectin inhibits liver neo-glucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and likely protects against the development of arteriosclerosis [5]. Leptin has the propriety to modulate TNF-alpha production and macrophage activation. We have strong evidence that TNF-alpha is over-expressed in adipose tissue of several animal models of obesity and has an important role in the pathogenesis of IR in these species. IL-6 secretion and release by human adipose tissue increases in obese patients. It leads to hepatic CRP synthesis and is involved in the onset of cardiovascular complications. Both TNFalpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signaling pathway. The
40 Tarantino: Diet and NAFLD pro-inflammatory effects of cytokines, through intracellular signaling pathways, involve the NF-kappaB and JNK systems. Genetic but also pharmacological manipulations of these effectors of the inflammatory response have been thought of as able to ameliorate insulin sensitivity in animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their antiinflammatory properties. In rodents, resistin can induce IR, while its implication in the control of insulin sensitivity is still a matter of debate in humans. It has been suggested that impaired skeletal muscle mitochondrial function may contribute to ectopic lipid deposition, obviously also in the liver, and the associated metabolic syndrome, by altering post-prandial energy storage. Recently, authors provided evidence that skeletal muscle mitochondrial function is preserved in patients with NAFLD, compared with age, BMI and fitness-matched healthy controls, and cannot account for ectopic fat deposition or the high prevalence of metabolic syndrome. This research confirms that factors other than skeletal muscle mitochondrial dysfunction play a role in NAFLD, suggesting that skeletal muscle and adipose tissue IR play a major role [6]. NAFLD is a multifactorial disease that involves a complex interaction of genetics, diet, and lifestyle, all of which combine to form the NAFLD phenotype. NAFLD – or generally speaking hepatic steatosis (HS) – is defined as the accumulation of lipid, primarily in the form of triacylglycerols in individuals who do not consume significant amounts of alcohol ( 30) may show features of hepatic stetosis, called by some authors lean NAFLD or better non-obese-NAFLD. Nevertheless the more severe form of this non-obese NAFLD, i.e., nonalcoholic steatohepatits (NASH) is characterized by a strong criterium of the metabolic syndrome, i.e., hypertension [7]. Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with simple FL and NASH [8], prompting to cure not only the more severe form, but also that once thought the benign form, i.e., FL. As aforementioned, recent data indicate that adipose tissue is the site of infiltrated macrophages, being a major source of locally-produced pro-inflammatory
cytokines, but also acting distantly. Accordingly, many efforts have been made to reduce inflammation and IR. The main mechanism proven to induce HS consists in the augmented process of lipolysis in adipose tissue, mainly in the visceral adipose tissue, which dramatically increases free fatty acid influx directly into the liver by the portal vein. Collaterally, a de novo synthesis of free fatty acids from liver has been ascertained with relative impact on their total amount. The free fatty acids lead to triglyceride synthesis and increased glucose production by altering the suppression of the release of hepatic glucose mediated by insulin. In addition, free fatty acids, ligands of the membrane-bound TLR4, promote per se inflammation [9]. Furthermore, body weight excess, particularly visceral, with its pro-inflammatory status, is strictly associated with NAFLD, even though inflammation is balanced by anti-inflammatory factors secreted by inflamed adipose tissue. Among them, adiponectin plays a key role. Fructose excess is thought to be a possible cause in inducing and worsening NAFLD, even though, on the basis of indirect comparisons across study findings, the apparent association between indexes of liver health (i.e., liver fat, hepatic de novo lipogenesis, ALT/AST, and γ-glutamyl transpeptase) and fructose or sucrose intake appear to be confounded by excessive energy intake. Overall, the available evidence is not sufficiently robust to draw conclusions regarding effects of fructose, HFCS, or sucrose consumption on NAFLD [10]. Bariatric surgery for severely obese patients as well as for those suffering from T2D are considered valid and safe alternative strategies to obtain weight loss and metabolic equilibrium and also the improvement of HS. Drugs have evidenced scarce or null effect in modifying ectopic fat in the liver. Recently, in contrast with the deluding findings of therapeutic approaches, regular aspirin use ( ≥ 15 times per month) may be associated with a lower prevalence of NAFLD, primarily among men and older patients [11]. A cornerstone of the management strategy in such patients with FL is the use of diet to decrease body weight, and improve IR, dyslipidemia and cardiovascular risks. Indeed, the target of reducing the visceral fat (obesity), considered a potential treatment strategy in order to cure NAFLD [12], and prevent or delay age-related diseases and to increase longevity [13], is generally thought to be a difficult one to meet. In fact, our Western society is progressively obese in part due to lack of exercise and increased availability of high-calorie dense food. As correctly emphasized in a recent review published [14], “NAFLD patients, whether obese or not, should be educated that a healthy diet and physical activity have benefits beyond weight reduction”. Although evidence
Tarantino: Diet and NAFLD 41
reiterates the difficulty in achieving success in every-day practice, drawing attention to alternative therapies for weight loss in NAFLD, the link between, a hypocaloric, hypoglicidic, hypolipidemic diet and NAFLD strongly conveys that a balanced nutrition could improve and/ or prevent NAFLD. Obviously, the correct diet of NAFLD patients can be achieved by the development of an appropriate nutrition composition/caloric balance. Among nutrients that play an important role in maintaining the liver metabolism the use of wine in low quantities should be mentioned. The effect of modest alcohol consumption on NAFLD does not seem to be exclusively associated with reduced IR or with the low prevalence of metabolic syndrome features. The liver protective effects of modest wine drinking are linked to reduction of triglyceride content of liver or an increase in circulating adiponectin, suggesting that the prevention of HS is mediated through AMPK and PPRAα. An intriguing mechanisms supports the role of enhanced activation of adiponectin receptor 2 in reducing liver fat. But, various other nutritional ingredients are reported to be useful, such as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all showing promising but not definite results. When dealing with the treatment of obesity-linked illnesses, in particular NAFLD, an emerging field of study is represented by prebiotics/ probiotics and restoration of normal gut flora, which could play a fundamental role in diet and its various components [15]. As a final comment, it is noteworthy to point out that both improving or reducing the severity of NAFLD bears a positive consequence on the evolution of atherosclerosis and its cardiovascular-associated disease, such as CAD, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature [16]. But, who could exclude the role of nutrition in modulating the acquired immunity in this condition?
References 1. Pi-Sunyer FX. The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 2002;10:97S–104S. 2. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol 2007;22:293–303. 3. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumié A,
Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clément K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgeryinduced weight loss. Diabetes 2005;54:2277–86. 4. Deng W, Wang X, Xiao J, Chen K, Zhou H, Shen D, Li H, Tang Q. Loss of regulator of g protein signaling 5 exacerbates obesity, hepatic steatosis, inflammation and insulin resistance. PLoS One 2012;7:e30256. 5. Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013;19:802–12. 6. Cuthbertson DJ, Irwin A, Sprung VS, Jones H, Pugh CJ, Daousi C, Adams VL, Bimson WE, Shojaee-Moradie F, Richardson P, Umpleby AM, Wilding JP, Kemp GJ. Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle. Clin Sci (Lond) 2014;127:655–63. 7. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, Srishord M. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore) 2012;91:319–27. 8. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of pairedbiopsy studies. Clin Gastroenterol Hepatol 2014;S1542–65. 9. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015–25. 10. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr 2014;100:833–49. 11. Shen H, Shahzad G, Jawairia M, Bostick RM, Mustacchia P. Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. Aliment Pharmacol Ther 2014;40:1066–73. 12. Finelli C, Tarantino G. Have guidelines addressing physical activity been established in nonalcoholic fatty liver disease? World J Gastroenterol 2012;18:6797–807. 13. Finelli C, Sommella L, Gioia S, La Sala N, Tarantino G. Should visceral fat be reduced to increase longevity? Ageing Res Rev 2013;12:996–1004. 14. Nseir W, Hellou E, Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:9338–44. 15. Tarantino G. Gut microbiome, obesity-related comorbidities, and low-grade chronic inflammation. J Clin Endocrinol Metab 2014;99:2343–6. 16. Tarantino G, Costantini S, Finelli C, Capone F, Guerriero E, La Sala N, Gioia S, Castello G. Carotid intima-media thickness is predicted by combined eotaxin levels and severity of hepatic steatosis at ultrasonography in obese patients with nonalcoholic Fatty liver disease. PLoS One 2014;9:105610.
Copyright of Hormone Molecular Biology & Clinical Investigation is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
