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Pathobiological and molecular connections involved in the high fructose and high fat diet induced diabetes associated nonalcoholic fatty liver disease

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Abstract

Background

Poor dietary habits such as an over consumption of high fructose and high fat diet are considered as the major culprit for the induction of diabetes associated liver injury. Diabetes mellitus is a metabolic disorder that affects various vital organs of the body especially the kidney, brain, heart, and liver. The high fructose and high fat (HFHF) diet worsen the metabolic conditions by producing various pathogenic burdens such as oxidative stress, inflammation, etc. on liver. The hyperlipidemic and hyperglycemic conditions induced by HFHF diet leads to the generation of various proinflammatory mediators like TNFα, interleukin and cytokines.

Aim and methods

The systematic bibliographical literature survey was done with the help of PubMed, Google scholar and MedLine to identify all pathological and molecular concerened with HFHF induced diabetic liver injury. The consumption of HFHF diet leads to an increase in mitochondrial oxidative stress thereby decreases the liver protective antioxidants required for cell viability. HFHF diet disturbs lipid and lipoprotein clearance by elevating the level of apolipoprotein CIII and impairing the hydrolysis of triglyceride. As a result, there is an increase in free fatty acid concentration, triglycerides and diacylglycerol in the liver which further triggers the situation of insulin resistance.

Conclusion

The focus of present review is based upon the various pathological, genetic and molecular mechanism involved in the development of high-fat high fructose diet induced diabetic liver injury. However, the current review also documented few shreds of evidence related to various microRNAs (miR-31, miR-33a, miR-34a, miR-144, miR-146b, miR-150) concerned to HFHF diet which play an important role in the pathogenesis of diabetes associated liver injury Dietary life style modification may prove beneficial in the management of various metabolic disorders.

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Abbreviations

ALT:

Alanine transaminase

AMPK:

AMP activated protein kinase

AST:

Aspartate aminotransferase

BBB:

Blood brain barrier

CCL2:

C–C Motif ligand 2

CXCL-8:

C–X–C Motif chemokine ligand 8

CCR2:

C–C chemokine receptor 2

DAG:

Diacylglycerol

IKK-β:

Inhibitor of kB kinase- β

DGAT:

Diacylglycerol acyltransferase

DLI:

Diabetic liver injury

FFA:

Free fatty acid

GLP:

Glucagon like peptide

GLUT1:

Glucose transporter 1

GR:

Glutathione reductase

HCC:

Hepato cellular carcinoma

HFHF:

High fructose high fat

IL:

Interleukin

IR:

Insulin resistance

IRS:

Insulin receptor substrate

JAK2-STAT3:

Janus-activating kinase2-signal transducer

KHK:

Ketohexokinase

LCAD:

Long chain l-3 hydroxy acyl-coA-enzyme

LPL:

Lipopolysaccharide

MCP-1:

Monocyte chemo attractant protein-1

MMP:

Matrix metalloproteinase

NAFLD:

Non alcoholic fatty liver disease

NASH:

Non alcoholic steatohepatitis

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

ROS:

Reactive oxygen species

SCFA:

Short chain fatty acid

SOD:

Superoxide dismutase

SOCS3:

Suppressor of cytokine signaling 3

Trx2:

Thioredoxin 2

Txnip:

Thioredoxin interacting protein

T2DM:

Type 2 diabetes mellitus

TG:

Triglyceride

TNF:

Tumor necrosis factor

TIMP1:

Tissue inhibitor of metalloproteinases

VLDL:

Very low density lipoprotein

References

  1. Dongiovanni P, Anstee Q, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19:5219–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Musso G, Gambino R, Cassader M, et al. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49.

    PubMed  Google Scholar 

  3. Kalra S, Vithalani M, Gulati G, et al. Study of prevalence of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes patients in India (SPRINT). J Assoc Physicians India. 2013;61:448–53.

    PubMed  Google Scholar 

  4. Trombetta M, Spiazzi G, Zoppini G, et al. type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther. 2005;22:24–7.

    PubMed  Google Scholar 

  5. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004;79:537–43.

    CAS  PubMed  Google Scholar 

  6. Jurgens H, Haass W, Castaneda TR, et al. Consuming fructose-sweetened beverages increases body adiposity in mice. Obes Res. 2005;13:1146.

    PubMed  Google Scholar 

  7. Kunde SS, Roede JR, Vos MB, et al. Hepatic oxidative stress in fructose-induced fatty liver is not caused by sulfur amino acid insufficiency. Nutrients. 2011;3:987–1002.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Nordberg J, Arnér ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med. 2001;31:287–312.

    Google Scholar 

  9. Patwari P, Lee RT. An expanded family of arrestins regulate metabolism. Trends Endocrinol Metab. 2012;23:216–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu N, Zheng B, Shaywitz A, et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013;49:1167–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hoehn KL, Salmon AB, Hohnen-Behrens C, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci. 2009;106:17787–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. De Luis DA, Aller R, Izaola O, et al. Effect of two different hypocaloric diets in transaminases and insulin resistance in nonalcoholic fatty liver disease and obese patients. Nutr Hosp. 2010;25:730–5.

    PubMed  Google Scholar 

  13. Chen Y, Yu M, Jones DP, et al. Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells. Toxicol Appl Pharmacol. 2006;216:256–62.

    CAS  PubMed  Google Scholar 

  14. Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339.

    CAS  PubMed  Google Scholar 

  15. Lubis AR, Widia F, Soegondo S, et al. The role of SOCS-3 protein in leptin resistance and obesity. Acta Med Indones. 2008;40:89–95.

    PubMed  Google Scholar 

  16. Vila L, Roglans N, Alegret M, et al. Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism. J Hepatol. 2008;48:1506–16.

    CAS  Google Scholar 

  17. Li JM, Li YC, Kong LD, et al. Curcumin inhibits hepatic protein-tyrosine phosphatase 1B and prevents hypertriglyceridemia and hepatic steatosis in fructose-fed rats. J Hepatol. 2010;51:1555–666.

    CAS  Google Scholar 

  18. Shapiro A, Mu W, Roncal C, et al. Fructose induced leptin resistance, exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol. 2008;295:1370–5.

    Google Scholar 

  19. Van Dam RM, Willett WC, Rimm EB, et al. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care. 2002;25:417–24.

    PubMed  Google Scholar 

  20. Stanhope KL. Sugar consumption, metabolic disease and obesity: the state of the controversy. Crit Rev Clin Lab Sci. 2016;53:52–67.

    CAS  PubMed  Google Scholar 

  21. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:34–40.

    Google Scholar 

  22. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Perla F, Prelati M, Lavorato M, et al. The role of lipid and lipoprotein metabolism in non-alcoholic fatty liver disease. Children. 2017;4:46.

    PubMed Central  Google Scholar 

  24. Mead JR, Irvine SA, Ramji DP. Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med. 2002;80:753–69.

    CAS  PubMed  Google Scholar 

  25. Teff KL, Elliott SS, Tschöp M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab. 2004;89:2963–72.

    CAS  PubMed  Google Scholar 

  26. Fried SK, Russell CD, Grauso NL, et al. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest. 1993;92:2191–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Shachter NS. Apolipoproteins CI and C-III as important modulators of lipoprotein metabolism. Curr Opin Lipidol. 2001;12:297–304.

    CAS  PubMed  Google Scholar 

  28. Su Q, Tsai J, Xu E, et al. Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance. J Hepatol. 2009;50:77–84.

    CAS  Google Scholar 

  29. Altomonte J, Cong L, Harbaran S, et al. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Investig. 2004;10:1493–503.

    Google Scholar 

  30. Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest. 2008;118:316–32.

    CAS  PubMed  Google Scholar 

  31. Savard C, Tartaglione EV, Kuver R, et al. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. J Hepatol. 2013;57:81–92.

    CAS  Google Scholar 

  32. Bedi O, Aggarwal S, Trehanpati N, et al. Molecular and pathological events involved in the pathogenesis of diabetes associated non-alcoholic fatty liver disease. J Clin Exp Pathol. 2019;9(5):607–18.

    Google Scholar 

  33. Sen T, Cawthon CR, Ihde BT, et al. Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity. Physiol Behav. 2017;173:305–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4.

    CAS  PubMed  Google Scholar 

  35. Houghton D, Stewart C, Day C, et al. Gut microbiota and lifestyle interventions in NAFLD. Int J Mol Sci. 2016;17:447.

    PubMed  PubMed Central  Google Scholar 

  36. Leung C, Rivera L, Furness JB, et al. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol. 2016;7:412.

    Google Scholar 

  37. Saez-Lara M, Robles-Sanchez C, Ruiz-Ojeda F, et al. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials. Int J Mol Sci. 2016;17:928.

    PubMed Central  Google Scholar 

  38. Di Baise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc. 2008;83:460–9.

    Google Scholar 

  39. Ley RE, Bäckhed F, Turnbaugh P, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci. 2005;102:11070–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Murphy EF, Cotter PD, Healy S, et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut. 2010;59:1635–42.

    CAS  PubMed  Google Scholar 

  41. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.

    CAS  PubMed  Google Scholar 

  42. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–103.

    CAS  PubMed  Google Scholar 

  43. Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol. 2012;11:440–9.

    CAS  PubMed  Google Scholar 

  44. Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery–induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;12:3049–57.

    Google Scholar 

  45. Nikkilä EA. Control of plasma and liver triglyceride kinetics by carbohydrate metabolism and insulin. J Lipid Res. 1969;7:63–134.

    Google Scholar 

  46. Naismith DJ, Rana IA. Sucrose and hyperlipidaemia. Ann Nutr Metab. 1974;16(4):238–48.

    CAS  Google Scholar 

  47. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes. 2005;54:73–8.

    Google Scholar 

  48. Boden G, Lebed B, Schatz M, et al. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001;50:1612–7.

    CAS  PubMed  Google Scholar 

  49. Ravikumar B, Carey PE, Snaar JE, et al. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am J Physiol Endocrinol Metab. 2005;288:789–97.

    Google Scholar 

  50. Itani SI, Ruderman NB, Schmieder F, et al. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes. 2002;51:2005–111.

    CAS  PubMed  Google Scholar 

  51. Liu L, Zhang Y, Chen N, et al. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest. 2007;117:1679–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2017;114:1752–61.

    Google Scholar 

  53. Meier JJ, Gethmann A, Götze O, et al. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia. 2006;49:452–8.

    CAS  PubMed  Google Scholar 

  54. Thomsen C, Storm H, Holst JJ, Hermansen K. Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes. Am J Clin Nutr. 2003;77:05–11.

    Google Scholar 

  55. Kuhre RE, Gribble FM, Hartmann B, et al. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans. Am J Physiol Gastrointest Liver Physiol. 2014;306:G622–G630630.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Trevaskis JL, Griffin PS, Wittmer C, et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2012;302:G762–G772772.

    CAS  PubMed  Google Scholar 

  57. Mells JE, Fu PP, Sharma S, et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol. 2011;302:G225–G23535.

    PubMed  PubMed Central  Google Scholar 

  58. Zhang L, Yang M, Ren H, et al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013;33:794–804.

    CAS  PubMed  Google Scholar 

  59. Sharma S, Mells JE, Fu PP, et al. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PloS one. 2011;6(9):e25269.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Tomas E, Stanojevic V, Habener JF. GLP-1-derived nonapeptide GLP-1 (28–36) amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept. 2011;167:177–84.

    CAS  PubMed  Google Scholar 

  61. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Cirillo P, Gersch MS, Mu W, et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. Clin J Am Soc Nephrol. 2009;20:45–53.

    Google Scholar 

  63. Chen Q, Wang T, Li J, et al. Effects of natural products on fructose-induced nonalcoholic fatty liver disease (NAFLD). Nutrients. 2017;9:96.

    PubMed Central  Google Scholar 

  64. Bergheim I, Weber S, Vos M, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J hepatol. 2008;48:983–92.

    CAS  PubMed  Google Scholar 

  65. Stojsavljević S, Palčić MG, Jukić LV, et al. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:18070.

    PubMed  PubMed Central  Google Scholar 

  66. Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes. 2005;54:114–24.

    Google Scholar 

  67. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006;17:4–12.

    CAS  PubMed  Google Scholar 

  68. Wullaert A, van Loo G, Heyninck K, et al. Hepatic tumor necrosis factor signaling and nuclear factor-κB: effects on liver homeostasis and beyond. Endocr Rev. 2007;28:365–86.

    CAS  PubMed  Google Scholar 

  69. Diehl AM, Li ZP, Lin HZ, et al. Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut. 2005;54:303–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bastard JP, Maachi M, van Nhieu JT, et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002;87:2084–9.

    CAS  PubMed  Google Scholar 

  71. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol. 2004;24:5434–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55:415–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sindhu S, Akhter N, Arefanian H, et al. Increased circulatory levels of fractalkine (CX3CL1) are associated with inflammatory chemokines and cytokines in individuals with type-2 diabetes. J Diabetes Metab Disorders. 2017;16:15.

    Google Scholar 

  75. Ito M, Suzuki J, Tsujioka S, et al. Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol Res. 2007;37:50–7.

    CAS  PubMed  Google Scholar 

  76. Jarrar MH, Baranova A, Collantes R, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412–21.

    CAS  PubMed  Google Scholar 

  77. Xu L, Kitade H, Ni Y, et al. Roles of chemokines and chemokine receptors in obesity-associated insulin resistance and nonalcoholic fatty liver disease. Biomolecules. 2015;5:1563–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rull A, Rodríguez F, Aragonès G, et al. Hepatic monocyte chemoattractant protein-1 is upregulated by dietary cholesterol and contributes to liver steatosis. Cytokine. 2009;48:273–9.

    CAS  PubMed  Google Scholar 

  79. Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116:115–24.

    CAS  PubMed  Google Scholar 

  80. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.

    CAS  PubMed  Google Scholar 

  81. Obstfeld AE, Sugaru E, Thearle M, et al. CC chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes. 2010;59:916–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Xi L, Qian Z, Xu G, et al. Beneficial impact of crocetin, a carotenoid from saffron, on insulin sensitivity in fructose-fed rats. J Nutr Biochem. 2007;18:64–72.

    CAS  PubMed  Google Scholar 

  83. Miller AW, Hoenig ME, Ujhelyi MR. Mechanisms of impaired endothelial function associated with insulin resistance. J Cardiovasc Pharmacol Ther. 1998;3:125–33.

    CAS  PubMed  Google Scholar 

  84. Nawrocki AR, Scherer PE. The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation. Curr Opin Pharmacol. 2004;4:281–9.

    CAS  PubMed  Google Scholar 

  85. Mackawy AM. Association of the+ 45T> G adiponectin gene polymorphism with insulin resistance in non-diabetic Saudi women. Gene. 2013;530:158–63.

    CAS  PubMed  Google Scholar 

  86. Shklyaev S, Aslanidi G, Tennant M, et al. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rat. Proc Natl Acad Sci. 2003;100:14217–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:9–83.

    Google Scholar 

  88. Hui JM, Hodge A, Farrell GC, et al. Beyond insulin resistance in NASH: TNF-α or adiponectin? J Hepatol. 2004;40:46–544.

    CAS  Google Scholar 

  89. Maeda N, Takahashi M, Funahashi T, et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–9.

    CAS  PubMed  Google Scholar 

  90. Kubota N, Terauchi Y, Yamauchi T, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277:25863–6.

    CAS  PubMed  Google Scholar 

  91. Wang Y, Zhou M, Lam KS, et al. Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications. Arq Bras Endocrinol Metabol. 2009;53:201–12.

    PubMed  Google Scholar 

  92. Pettinelli P, Videla LA. Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011;96:1424–30.

    CAS  PubMed  Google Scholar 

  93. Bundalo M, Zivkovic M, Culafic T, et al. Oestradiol treatment counteracts the effect of fructose-rich diet on matrix metalloproteinase 9 expression and NF [kappa] B activation. Folia Boil. 2015;61:233.

    CAS  Google Scholar 

  94. Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. New York: Thieme Medical Publishers; 2001. p. 584–4662.

    Google Scholar 

  95. Hemmann S, Graf J, Roderfeld M, et al. Expression of MMPs and TIMPs in liver fibrosis—a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol. 2007;46:955–75.

    CAS  PubMed  Google Scholar 

  96. Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev. 2001;81:1031–64.

    CAS  PubMed  Google Scholar 

  97. Statnick MA, Beavers LS, Conner LJ, et al. Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes. Exp Diabetes Res. 2000;1:81–8.

    CAS  Google Scholar 

  98. Ljumovic D, Diamantis I, Alegakis AK, et al. Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases. Clin Chim Acta. 2004;349:203–11.

    CAS  PubMed  Google Scholar 

  99. Wanninger J, Walter R, Bauer S, et al. MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis. Exp Mol Pathol. 2011;91:603–7.

    CAS  PubMed  Google Scholar 

  100. Cao Q, Mak KM, Lieber CS. Leptin represses matrix metalloproteinase-1 gene expression in LX2 human hepatic stellate cells. J hepatol. 2007;46:124–33.

    CAS  PubMed  Google Scholar 

  101. Hou JF, Wang XG, Wei J. Alteration of liver MMP-9/TIMP-1 and plasma type IV collagen in the development of rat insulin resistance. In: Frontier and future development of information technology in medicine and education. Dordrecht: Springer; 2014. p. 531–43. ISBN 978-94-007-7618-0.

    Google Scholar 

  102. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998;35:353–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Willner IR, Waters B, Patil SR, et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol. 2001;96:2957.

    CAS  PubMed  Google Scholar 

  104. Anstee QM, Daly AK, Day CP. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin Liver Dis. 2011;31:128–46.

    CAS  PubMed  Google Scholar 

  105. Kohjima M, Enjoji M, Higuchi N, et al. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. 2007;20:351–8.

    CAS  PubMed  Google Scholar 

  106. Zain SM, Mohamed R, Mahadeva S, et al. A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Hum Genet. 2012;131:1145–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Havel PJ. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev. 2005;63:133–57.

    PubMed  Google Scholar 

  108. Nagai Y, Yonemitsu S, Erion DM, et al. The role of peroxisome proliferator-activated receptor γ coactivator-1 β in the pathogenesis of fructose-induced insulin resistance. Cell metab. 2009;9:252–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bergman RN, Kim SP, Hsu IR, et al. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Am J Med. 2007;120:S3–8.

    CAS  PubMed  Google Scholar 

  110. Fontana L, Eagon JC, Trujillo ME, et al. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–3.

    CAS  PubMed  Google Scholar 

  111. Van Den Berghe G, Bronfman M, Vanneste R, Hers HG. The mechanism of adenosine triphosphate depletion in the liver after a load of fructose. A kinetic study of liver adenylate deaminase. Biochem J. 1977;162:601–9.

    PubMed  PubMed Central  Google Scholar 

  112. Khitan Z, Kim DH. Fructose: a key factor in the development of metabolic syndrome and hypertension. Med J Nutrition Metab. 2013. https://doi.org/10.1155/2013/68267.

    Article  Google Scholar 

  113. Abdelmalek MF, Lazo M, Horska A, Fatty Liver Subgroup of the Look AHEAD Research Group, et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. J Hepatol. 2012;56:952–60.

    CAS  Google Scholar 

  114. Parks EJ, Hellerstein MK. Carbohydrate-induced hyper triacylglycerolemia: historical perspective and review of biological mechanisms. Am J Clin Nutr. 2000;71:412–33.

    CAS  PubMed  Google Scholar 

  115. Boden G, Chen X, Rosner J, et al. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995;44:1239–42.

    CAS  PubMed  Google Scholar 

  116. Pagliassotti MJ. Sucrose, insulin action and biologic complexity. Rec Res Dev Physiol. 2004;2:337–53.

    CAS  Google Scholar 

  117. Bantle JP, Raatz SK, Thomas W, et al. Effects of dietary fructose on plasma lipids in healthy subjects. Am J Clin Nutr. 2000;72:1128–34.

    CAS  PubMed  Google Scholar 

  118. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Johnson RJ, Segal MS, Sautin Y, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007;86:899–906.

    CAS  PubMed  Google Scholar 

  120. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterol. 2007;132:2169–80.

    CAS  Google Scholar 

  121. de Moura RF, Ribeiro C, de Oliveira JA, et al. Metabolic syndrome signs in Wistar rats submitted to different high-fructose ingestion protocols. Br J Nutr. 2008;101:1178–84.

    PubMed  Google Scholar 

  122. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433–8.

    PubMed  Google Scholar 

  123. Abid A, Taha O, Nseir W, et al. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J hepatol. 2009;51:918–24.

    CAS  PubMed  Google Scholar 

  124. Yang S, Zhu H, Li Y, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378:259–68.

    CAS  PubMed  Google Scholar 

  125. Aguirre V, Uchida T, Yenush L, et al. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem. 2009;275:047–54.

    Google Scholar 

  126. Mantena SK, Vaughn DP, Andringa KK, et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. J Biol Chem. 2009;417:183–93.

    CAS  Google Scholar 

  127. Marchesini G, Brizi M, Bianchi G, et al. Metformin in nonalcoholic steatohepatitis. Lancet. 2001;358:893–4.

    CAS  PubMed  Google Scholar 

  128. Nair S, Diehl AM, Wiseman M, et al. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–8.

    CAS  PubMed  Google Scholar 

  129. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. J Hepatol. 2004;39:188–96.

    CAS  Google Scholar 

  131. Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;32:66–75.

    Google Scholar 

  132. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015;3(1):5.

    PubMed  PubMed Central  Google Scholar 

  133. Salic K, Kleemann R, Wilkins-Port C, et al. Apical sodium-dependent bile acid transporter inhibition with volixibat improves metabolic aspects and components of non-alcoholic steatohepatitis in Ldlr−/− Leiden mice. PLoS One. 2019;14(6):e0218459.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mu J, Pinkstaff J, Li Z, et al. FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes. 2012;61:505–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519.

    CAS  PubMed  Google Scholar 

  136. Luyckx FH, Desaive C, Thiry A, et al. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes. 1998;22:222.

    CAS  Google Scholar 

  137. Dushay J, Lai M. Is trimming the fat enough? Fibroblast growth factor 21 as an emerging treatment for nonalcoholic fatty liver disease. Hepatology. 2019;70(5):1860–2.

    PubMed  Google Scholar 

  138. Buko VU, Kuzmitskaya-Nikolaeva IA, Naruta EE, et al. Ursodeoxycholic acid dose-dependently improves liver injury in rats fed a methionine-and choline-deficient diet. Hepatol Res. 2011;4:647–59.

    Google Scholar 

  139. McCarthy EM, Rinella ME. The role of diet and nutrient composition in nonalcoholic fatty liver disease. J Acad Nutr Diet. 2012;112:401–9.

    CAS  PubMed  Google Scholar 

  140. Ryan MC, Abbasi F, Lamendola C, et al. Serum alanine aminotransferase levels decrease further with carbohydrate than fat restriction in insulin-resistant adults. Diabetes Care. 2007;30:1075–80.

    CAS  PubMed  Google Scholar 

  141. Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–46.

    PubMed  Google Scholar 

  142. Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. J Hepatol. 2001;34:745–50.

    CAS  Google Scholar 

  143. Tuomola M, Vahva M, Kallio H. High-performance liquid chromatography determination of skatole and indole levels in pig serum, subcutaneous fat, and submaxillary salivary glands. J Agric Food Chem. 1996;44:1265–70.

    CAS  Google Scholar 

  144. Karnik S, Charlton M, Li L, et al. Efficacy of an ASK1 inhibitor to reduce fibrosis and steatosis in a murine model of NASH is associated with normalization of lipids and hepatic gene expression and a reduction in serum biomarkers of inflammation and fibrosis. J Hepatol. 2015;62(5).

  145. Loomba R, Lawitz E, Mantry PS, et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. J Hepatol. 1120A;64:1119A–20A.

    Google Scholar 

  146. Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol. 2008;23:1635–48.

    PubMed  Google Scholar 

  147. Lim JS, Mietus-Snyder M, Valente A, et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7:251–64.

    CAS  PubMed  Google Scholar 

  148. Lee JS, Jun DW, Kim EK, et al. Histologic and metabolic derangement in high-fat, high-fructose, and combination diet animal models. Sci World J. 2015. https://doi.org/10.1155/2015/306326.

    Article  Google Scholar 

  149. Engel MM, Kusumastuty I, Anita KW, et al. The effect of high fat high fructose diet (modification of AIN-93M) on nuclear factor kappa beta expression in the liver tissue of male Sprague Dawley rats. J Phys Conf Ser. 2019;1374:012042.

    Google Scholar 

  150. Barrière DA, Noll C, Roussy G, Lizotte F, Kessai A, Kirby K, et al. Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications. Sci Rep. 2018;8:424.

    PubMed  PubMed Central  Google Scholar 

  151. Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, et al. High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr Metab. 2016;13:15.

    Google Scholar 

  152. Clapper JR, Hendricks MD, Gu G, et al. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am J Physiol Gastrointest Liver Physiol. 2013;305:G483–G495495.

    CAS  PubMed  Google Scholar 

  153. Zaki SM, Fattah SA, Hassan DS. The differential effects of high-fat and high–fructose diets on the liver of male albino rat and the proposed underlying mechanisms. Folia Morphol. 2019;78:24–36.

    Google Scholar 

  154. Wada T, Kenmochi H, Miyashita Y, et al. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology. 2010;151:2040–9.

    CAS  PubMed  Google Scholar 

  155. Kohli R, Kirby M, Xanthakos SA, et al. High-fructose, medium chain trans-fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. J Hepatolol. 2010;52:934–44.

    CAS  Google Scholar 

  156. Abdelmalek MF, Suzuki A, Guy C, Nonalcoholic Steatohepatitis Clinical Research Network, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. J Hepatol. 2010;51:1961–71.

    CAS  Google Scholar 

  157. Hsieh FC, Lee CL, Chai CY, et al. Oral administration of Lactobacillus reuteri GMNL-263 improves insulin resistance and ameliorates hepatic steatosis in high fructose-fed rats. Nutr Metab. 2013;10:35.

    CAS  Google Scholar 

  158. Gerhard GS, DiStefano JK. Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol. 2015;27:226.

    Google Scholar 

  159. Alvarez ML, DiStefano JK. Towards microRNA-based therapeutics for diabetic nephropathy. Diabetologia. 2013;56:444–56.

    CAS  PubMed  Google Scholar 

  160. Cheung O, Puri P, Eicken C. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. J Hepatol. 2008;48:1810–20.

    CAS  Google Scholar 

  161. Vega-Badillo J, Gutiérrez-Vidal R, Hernández-Pérez HA, et al. Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int. 2016;36:1383–91.

    CAS  PubMed  Google Scholar 

  162. Wen J, Friedman JR. miR-122 regulates hepatic lipid metabolism and tumor suppression. J Clin Investig. 2012;122:2773–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203.

    CAS  PubMed  Google Scholar 

  164. Sud N, Zhang H, Pan K, et al. Aberrant expression of microRNA induced by high-fructose diet: implications in the pathogenesis of hyperlipidemia and hepatic insulin resistance. J Nutr Biochem. 2017;43:125–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Tessitore A, Cicciarelli G, Del Vecchio F, et al. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice. BMC Cancer. 2016;16:3.

    PubMed  PubMed Central  Google Scholar 

  166. Kalaki-Jouybari F, Shanaki M, Delfan M, et al. High-intensity interval training (HIIT) alleviated NAFLD feature via miR-122 induction in liver of high-fat high-fructose diet induced diabetic rats. Arch Physiol Biochem. 2018;3:1–8.

    Google Scholar 

  167. Hanousková B, Neprašová B, Skálová L, et al. High-fructose drinks affect microRNAs expression differently in lean and obese mice. J Nutr Biochem. 2019;68:42–50.

    PubMed  Google Scholar 

  168. Chyau CC, Wang HF, Zhang WJ, et al. Antrodan alleviates high-fat and high-fructose diet-induced fatty liver disease in C57BL/6 Mice Model via AMPK/Sirt1/SREBP-1c/PPARγ pathway. Int J Mol Sci. 2020;21:360.

    PubMed Central  Google Scholar 

  169. Stephenson K, Kennedy L, Hargrove L, et al. Updates on dietary models of nonalcoholic fatty liver disease: current studies and insights. Gene Exp J Liver Res. 2018;18:5–17.

    CAS  Google Scholar 

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We acknowledge and extend our thanks to the management of Chitkara University for providing facilities and continuous support.

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  1. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Ekta, Manisha Gupta, Amarjot Kaur, Thakur Gurjeet Singh & Onkar Bedi

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Ekta, Gupta, M., Kaur, A. et al. Pathobiological and molecular connections involved in the high fructose and high fat diet induced diabetes associated nonalcoholic fatty liver disease. Inflamm. Res. 69, 851–867 (2020). https://doi.org/10.1007/s00011-020-01373-7

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