Exploration of Medicine

Table 1. Sexually dimorphic hepatic genes associated with NAFLD

Gene	Function (s)	Model (s) Used	Female	Male	Effect (s)
JNK	Transcription factor; regulate fatty acid oxidation; improve insulin sensitivity	SHROB Rats	↑↑	↑	Less severe steatosis in females
AMPK	Transcription factor; regulate fatty acid oxidation; improve insulin sensitivity	SHROB Rats	↑↑	↑	Less severe steatosis in females
CD36	Receptor; promotes fatty acid uptake into muscle and adipose tissues; fatty acid transport, β-oxidation	SHROB Rats; FXR-deficient mice; C57BL6/J HFD Mice	↑↑	↑	Less severe steatosis in females
PPARγ	Transcription factor; activates SREBP-1c, a master transcription factor that promotes de novo lipid synthesis (DNL)	SHROB Rats	↑	↑↑	More severe steatosis and inflammation in males
PNPLA3	Enzyme; involved in the accumulation of lipid droplets; esterification	SHROB Rats; C57BL6/J HFD Mice	↑	↑↑	More severe steatosis and inflammation in males
AQP7	The main channel in facilitating the release of lipolytic glycerol from adipocytes	C57BL/6 HFD mice, streptozotocin-induced DM rats	↑↑	↑	Increase plasma glycerol levels in both sexes
AQP9	The principal facilitative pathway in liver uptake of glycerol	C57BL/6 HFD mice, streptozotocin-induced DM rats	↓↓ (Expression and glycerol permeability)	↓	Less severe steatosis and hyperglycemia in females

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SHROB: obese spontaneously hypertensive; ↑ increased; ↑↑ highly increased; ↓ decreased; ↓↓ highly decreased

Declarations

Author contributions

NCS; PJG; CT and NR contributed conception and design of the review and in the writing of the different sections of the review. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

NCS is funded by the Department of Science and Technology-Philippine Council for Health Research and Development (DOST-PCHRD), Philippines; PJG is supported by Post-doctoral Fellowships 2020 from Fondazione Umberto Veronesi, Italy; NR is funded by Fondazione Cassa di Risparmio di Trieste (CRTrieste) and by Fondazione Italiana Fegato ONLUS.

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References

Rosso N, Chavez-Tapia NC, Tiribelli C, Bellentani S. Translational approaches: from fatty liver to non-alcoholic steatohepatitis. World J Gastroenterol. 2014;20:9038–49. [DOI] [PubMed] [PMC]

Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827–38. [DOI] [PubMed]

Araújo AR, Rosso N, Bedogni G, Tiribelli C, Bellentani S. Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: what we need in the future. Liver Int. 2018;38 Suppl 1:47–51. [DOI] [PubMed]

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20. [DOI] [PubMed]

Lonardo A, Suzuki A. Nonalcoholic fatty liver disease: does sex matter? Hepatobiliary Surg Nutr. 2019;8:164–6. [DOI] [PubMed] [PMC]

Lonardo A, Nascimbeni F, Ballestri S, Fairweather D, Win S, Than TA, et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology. 2019;70:1457–69. [DOI] [PubMed] [PMC]

Hamaguchi M, Kojima T, Ohbora A, Takeda N, Fukui M, Kato T. Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women. World J Gastroenterol. 2012;18:237–43. [DOI] [PubMed] [PMC]

Wang Z, Xu M, Hu Z, Shrestha UK. Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. Menopause. 2015;22:667–73. [DOI] [PubMed]

Waxman DJ, Celenza JL. Sexual dimorphism of hepatic gene expression: novel biological role of KRAB zinc finger repressors revealed. Genes Dev. 2003;17:2607–13. [DOI] [PubMed]

10.

Molinar-Toribio E, Pérez-Jiménez J, Ramos-Romero S, Lluís L, Sánchez-Martos V, Taltavull N, et al. Cardiovascular disease-related parameters and oxidative stress in SHROB Rats, a model for metabolic syndrome. PLoS One. 2014;9:e104637. [DOI] [PubMed] [PMC]

11.

Yen TT, Shaw WN, Yu PL. Genetics of obesity in Zucker rats and Koletsky rats. Heredity. 1977;38:373–7. [DOI] [PubMed]

12.

Dong Q, Kuefner MS, Deng X, Bridges D, Park EA, Elam MB, et al. Sex-specific differences in hepatic steatosis in obese spontaneously hypertensive (SHROB) rats. Biol Sex Differ. 2018;9:40. [DOI] [PubMed] [PMC]

13.

Yamashita H, Takenoshita M, Sakurai M, Bruick RK, Henzel WJ, Shillinglaw W, et al. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci U S A. 2001;98:9116–21. [DOI] [PubMed] [PMC]

14.

Hirano K, Kuwasako T, Nakagawa-Toyama Y, Janabi M, Yamashita S, Matsuzawa Y. Pathophysiology of human genetic CD36 deficiency. Trends Cardiovasc Med. 2003;13:136–41. [DOI] [PubMed]

15.

Sheng L, Jena PK, Liu HX, Kalanetra KM, Gonzalez FJ, French SW, et al. Gender differences in bile acids and microbiota in relationship with gender dissimilarity in steatosis induced by diet and FXR inactivation. Sci Rep. 2017;7:1748. [DOI] [PubMed] [PMC]

16.

Wankhade UD, Zhong Y, Kang P, Alfaro M, Chintapalli SV, Piccolo BD, et al. Maternal high-fat diet programs offspring liver steatosis in a sexually dimorphic manner in association with changes in gut microbial ecology in mice. Sci Rep. 2018;8:16502. [DOI] [PubMed] [PMC]

17.

Jiao Y, Lu Y, Li X. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin. 2015;36:44–50. [DOI] [PubMed] [PMC]

18.

Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol. 2008;14:22–8. [DOI] [PubMed] [PMC]

19.

Kim JB, Spiegelman BM. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 1996;10:1096–107. [DOI] [PubMed]

20.

Smagris E, BasuRay S, Li J, Huang Y, Lai KV, Gromada J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61:108–18. [DOI] [PubMed] [PMC]

21.

Fuchs CD, Claudel T, Trauner M. Role of metabolic lipases and lipolytic metabolites in the pathogenesis of NAFLD. Trends Endocrinol Metab. 2014;25:576–85. [DOI] [PubMed]

22.

Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107:7892–7. [DOI] [PubMed] [PMC]

23.

BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A. 2019;116:9521–6. [DOI] [PubMed] [PMC]

24.

Mancina RM, Matikainen N, Maglio C, Söderlund S, Lundbom N, Hakkarainen A, et al. Paradoxical dissociation between hepatic fat content and de novo lipogenesis due to PNPLA3 sequence variant. J Clin Endocrinol Metab. 2015;100:E821–5. [DOI] [PubMed]

25.

Rodríguez A, Marinelli RA, Tesse A, Frühbeck G, Calamita G. Sexual dimorphism of adipose and hepatic aquaglyceroporins in health and metabolic disorders. Front Endocrinol. 2015;6:171. [DOI]

26.

Schmidt SL, Bessesen DH, Stotz S, Peelor FF, Miller BF, Horton TJ. Adrenergic control of lipolysis in women compared with men. J Appl Physiol. 2014;117:1008–19. [DOI] [PubMed] [PMC]

27.

Rodríguez A, Catalán V, Gómez-Ambrosi J, García-Navarro S, Rotellar F, Valentí V, et al. Insulin- and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade. J Clin Endocrinol Metab. 2011;96:E586–97. [DOI] [PubMed]

28.

Calamita G, Gena P, Ferri D, Rosito A, Rojek A, Nielsen S, et al. Biophysical assessment of aquaporin-9 as principal facilitative pathway in mouse liver import of glucogenetic glycerol. Biol Cell. 2012;104:342–51. [DOI] [PubMed]

29.

Lebeck J, Gena P, O’Neill H, Skowronski MT, Lund S, Calamita G, et al. Estrogen prevents increased hepatic aquaporin-9 expression and glycerol uptake during starvation. Am J Physiol Gastrointest Liver Physiol. 2012;302:G365–74. [DOI] [PubMed]

30.

Nicchia GP, Frigeri A, Nico B, Ribatti D, Svelto M. Tissue distribution and membrane localization of aquaporin-9 water channel: evidence for sex-linked differences in liver. J Histochem Cytochem. 2001;49:1547–56. [DOI] [PubMed]

31.

Rojek AM, Skowronski MT, Füchtbauer EM, Füchtbauer AC, Fenton RA, Agre P, et al. Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice. Proc Natl Acad Sci U S A. 2007;104:3609–14. [DOI] [PubMed] [PMC]

32.

Spegel P, Chawade A, Nielsen S, Kjellbom P, Rützler M. Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice. Physiol Rep. 2015;3:e12538. [DOI] [PubMed] [PMC]

33.

Portois L, Zhang Y, Ladrière L, Perret J, Louchami K, Gaspard N, et al. Perturbation of glycerol metabolism in hepatocytes from n3-PUFA-depleted rats. Int J Mol Med. 2012;29:1121–6. [DOI] [PubMed]

34.

Cai C, Wang C, Ji W, Liu B, Kang Y, Hu Z, et al. Knockdown of hepatic aquaglyceroporin-9 alleviates high fat diet-induced non-alcoholic fatty liver disease in rats. Int Immunopharmacol. 2013;15:550–6. [DOI] [PubMed]

35.

Rodríguez A, Gena P, Méndez-Giménez L, Rosito A, Valentí V, Rotellar F, et al. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes (Lond). 2014;38:1213–20. [DOI] [PubMed]

36.

Pan JJ, Fallon MB. Gender and racial differences in nonalcoholic fatty liver disease. World J Hepatol. 2014;6:274–83. [DOI] [PubMed] [PMC]

37.

Summart U, Thinkhamrop B, Chamadol N, Khuntikeo N, Songthamwat M, Kim CS. Gender differences in the prevalence of nonalcoholic fatty liver disease in the Northeast of Thailand: a population-based cross-sectional study. F1000Res. 2017;6:1630. [DOI] [PubMed] [PMC]

38.

Yang JD, Abdelmalek MF, Pang H, Guy CD, Smith AD, Diehl AM, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology. 2014;59:1406–14. [DOI] [PubMed] [PMC]

39.

Zhang H, Liu Y, Wang L, Li Z, Zhang H, Wu J, et al. Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the malerat. J Lipid Res. 2013;54:345–57. [DOI] [PubMed] [PMC]

40.

Mc Auley MT, Mooney KM. Lipid metabolism and hormonal interactions: impact on cardiovascular disease and healthy aging. Expert Rev Endocrinol Metab. 2014;9:357–67. [DOI] [PubMed]

41.

Gil-Campos M, Cañete R, Gil A. Hormones regulating lipid metabolism and plasma lipids in childhood obesity. Int J Obes Relat Metab Disord. 2004;28 Suppl 3:S75–80. [DOI] [PubMed]

42.

Palmisano BT, Zhu L, Eckel RH, Stafford JM. Sex differences in lipid and lipoprotein metabolism. Mol Metab. 2018;15:45–55. [DOI] [PubMed] [PMC]

43.

Camporez JP, Lyu K, Goldberg EL, Zhang D, Cline GW, Jurczak MJ, et al. Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance. J Physiol. 2019;597:3885–903. [DOI] [PubMed] [PMC]

44.

Palmisano BT, Zhu L, Stafford JM. Role of estrogens in the regulation of liver lipid metabolism. Adv Exp Med Biol. 2017;1043:227–56. [DOI] [PubMed] [PMC]

45.

Barakat R, Oakley O, Kim H, Jin J, Ko CJ. Extra-gonadal sites of estrogen biosynthesis and function. BMB Rep. 2016;49:488–96. [DOI] [PubMed] [PMC]

46.

Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017;97:995–1043. [DOI] [PubMed] [PMC]

47.

Pupo M, Maggiolini M, Musti AM. GPER mediates non-genomic effects of estrogen. Methods Mol Biol. 2016;1366:471–88. [DOI] [PubMed]

48.

Yaşar P, Ayaz G, User SD, Güpür G, Muyan M. Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol. 2016;16:4–20. [DOI] [PubMed] [PMC]

49.

Qiu S, Vazquez JT, Boulger E, Liu H, Xue P, Hussain MA, et al. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males. Sci Rep. 2017;7:1661. [DOI] [PubMed] [PMC]

50.

Zhou Y, Shimizu I, Lu G, Itonaga M, Okamura Y, Shono M, et al. Hepatic stellate cells contain the functional estrogen receptor beta but not the estrogen receptor alpha in male and female rats. Biochem Biophys Res Commun. 2001;286:1059–65. [DOI] [PubMed]

51.

Gao H, Fält S, Sandelin A, Gustafsson JÅ, Dahlman-Wright K. Genome-wide identification of estrogen receptor α-binding sites in mouse liver. Mol Endocrinol. 2008;22:10–22. [DOI] [PubMed] [PMC]

52.

Villa A, Torre SD, Stell A, Cook J, Brown M, Maggi A. Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition. Proc Natl Acad Sci U S A. 2012;109:11806–11. [DOI] [PubMed] [PMC]

53.

Chen KL, Madak-Erdogan Z. Estrogens and female liver health. Steroids. 2018;133:38–43. [DOI] [PubMed]

54.

Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A. 2000;97:12729–34. [DOI] [PubMed] [PMC]

55.

Bitoska I, Krstevska B, Milenkovic T, Subeska-Stratrova S, Petrovski G, Mishevska SJ, et al. Effects of hormone replacement therapy on insulin resistance in postmenopausal diabetic women. Open Access Maced J Med Sci. 2016;4:83–8. [DOI] [PubMed] [PMC]

56.

Gupte AA, Pownall HJ, Hamilton DJ. Estrogen: an emerging regulator of insulin action and mitochondrial function. J Diabetes Res. 2015;2015:916585. [DOI] [PubMed] [PMC]

57.

Saraç F, Saydam G, Sahin F, Oztekin K, Saygili F, Tüzün M, et al. Effects of hormone replacement therapy on insulin resistance and platelet function tests. Med Princ Pract. 2009;18:43–7. [DOI] [PubMed]

58.

Venetsanaki V, Polyzos SA. Menopause and non-alcoholic fatty liver disease: a review focusing on therapeutic perspectives. Curr Vasc Pharmacol. 2019;17:546–55. [DOI] [PubMed]

59.

Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, et al. Metabolic actions of estrogen receptor beta (ERβ) are mediated by a negative cross-talk with PPARγ. PLoS Genet. 2008;4:e1000108. [DOI] [PubMed] [PMC]

60.

Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, et al. Obesity and disturbed lipoprotein profile in estrogen receptor-α-deficient male mice. Biochem Biophys Res Commun. 2000;278:640–5. [DOI] [PubMed]

61.

Sharma G, Prossnitz ER. G-protein-coupled estrogen receptor (GPER) and sex-specific metabolic homeostasis. Adv Exp Med Biol. 2017;1043:427–53. [DOI] [PubMed] [PMC]

62.

Meoli L, Isensee J, Zazzu V, Nabzdyk CS, Soewarto D, Witt H, et al. Sex- and age-dependent effects of Gpr30 genetic deletion on the metabolic and cardiovascular profiles of diet-induced obese mice. Gene. 2014;540:210–6. [DOI] [PubMed]

63.

Davis KE, Carstens EJ, Irani BG, Gent LM, Hahner LM, Clegg DJ. Sexually dimorphic role of G proteincoupled estrogen receptor (GPER) in modulating energy homeostasis. Horm Behav. 2014;66:196–207. [DOI] [PubMed] [PMC]

64.

Wang A, Luo J, Moore W, Alkhalidy H, Wu L, Zhang J, et al. GPR30 regulates diet-induced adiposity in female mice and adipogenesis in vitro. Sci Rep. 2016;6:34302. [DOI] [PubMed] [PMC]

65.

Mody A, White D, Kanwal F, Garcia JM. Relevance of low testosterone to non-alcoholic fatty liver disease. Cardiovasc Endocrinol. 2015;4:83–9. [DOI] [PubMed] [PMC]

66.

Tyagi V, Scordo M, Yoon RS, Liporace FA, Greene LW. Revisiting the role of testosterone: are we missing something? Rev Urol. 2017;19:16–24. [DOI] [PubMed] [PMC]

67.

Yassin A, Doros G. Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes. 2013;3:73–83. [DOI] [PubMed] [PMC]

68.

Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009;5:673–81. [DOI] [PubMed]

69.

Moulana M, Lima R, Reckelhoff JF. Metabolic syndrome, androgens, and hypertension. Curr Hypertens Rep. 2011;13:158–62. [DOI] [PubMed] [PMC]

70.

Navarro G, Allard C, Xu W, Mauvais‐Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity. 2015;23:713–9. [DOI] [PubMed] [PMC]

71.

Jaruvongvanich V, Sanguankeo A, Riangwiwat T, Upala S. Testosterone, sex hormone-binding globulin and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Ann Hepatology. 2017;16:382–94.

72.

Kim S, Kwon H, Park JH, Cho B, Kim D, Oh SW, et al. A low level of serum total testosterone is independently associated with nonalcoholic fatty liver disease. BMC Gastroenterology. 2012;12:69. [DOI] [PubMed] [PMC]

73.

Sarkar M, Yates K, Suzuki A, Lavine J, Gill R, Ziegler T, et al. Low testosterone is associated with nonalcoholic steatohepatitis (NASH) and severity of NASH fibrosis in men with NAFLD. Clin Gastroenterol Hepatol. 2019;[Epub ahead of print]. [DOI]

74.

Yim JY, Kim J, Kim D, Ahmed A. Serum testosterone and non-alcoholic fatty liver disease in men and women in the US. Liver Int. 2018;38:2051–9. [DOI] [PubMed]

75.

Addison ML, Rissman EF. Sexual dimorphism of growth hormone in the hypothalamus: regulation by estradiol. Endocrinology. 2012;153:1898–907. [DOI] [PubMed] [PMC]

76.

Lichanska AM, Waters MJ. How growth hormone controls growth, obesity and sexual dimorphism. Trends Genet. 2008;24:41–7. [DOI] [PubMed]

77.

Henry RK. Growth hormone deficiency and nonalcoholic fatty liver disease with insights from humans and animals: pediatric implications. Metab Syndr Relat Disord. 2018;16:507–13. [DOI]

78.

Takahashi Y. The role of growth hormone and insulin-like growth factor-I in the liver. Int J Mol Sci. 2017;18:E1447. [DOI] [PubMed] [PMC]

79.

Jansson JO, Edén S, Isaksson O. Sexual dimorphism in the control of growth hormone secretion. Endocr Rev. 1985;6:128–50. [DOI] [PubMed]

80.

Ceseña TI, Cui TX, Piwien-Pilipuk G, Kaplani J, Calinescu AA, Huo JS, et al. Multiple mechanisms of growth hormone-regulated gene transcription. Mol Genet Metab. 2007;90:126–33. [DOI] [PubMed] [PMC]

81.

Oshida K, Vasani N, Waxman DJ, Corton JC. Disruption of STAT5b-regulated sexual dimorphism of the liver transcriptome by diverse factors is a common event. PLoS One. 2016;11:e0148308. [DOI] [PubMed] [PMC]

82.

Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A. 1997;94:7239–44. [DOI] [PubMed] [PMC]

83.

Vidarsdottir S, Walenkamp MJ, Pereira AM, Karperien M, van Doorn J, van Duyvenvoorde HA, et al. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J Clin Endocrinol Metab. 2006;91:3482–5. [DOI] [PubMed]

84.

Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ, Waxman DJ. Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. Mol Endocrinol. 2006;20:1333–51. [DOI] [PubMed]

85.

Oshida K, Waxman DJ, Corton JC. Chemical and hormonal effects on STAT5b-dependent sexual dimorphism of the liver transcriptome. PLoS One. 2016;11:e0150284. [DOI] [PubMed] [PMC]

86.

Vidal OM, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia DJ, Woelfle J, et al. In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. Mol Endocrinol. 2007;21:293–311. [DOI] [PubMed]

87.

Villanueva-Ortega E, Garcés-Hernández MJ, Herrera-Rosas A, López-Alvarenga JC, Laresgoiti-Servitje E, Escobedo G, et al. Gender-specific differences in clinical and metabolic variables associated with NAFLD in a Mexican pediatric population. Ann Hepatol. 2019;18:693–700. [DOI] [PubMed]

88.

Van Sinderen M, Steinberg G, Jorgensen SB, Honeyman J, Chow JDY, Simpson ER, et al. Sexual dimorphism in the glucose homeostasis phenotype of the Aromatase Knockout (ArKO) mice. J Steroid Biochem Mol Biol. 2017;170:39–48. [DOI] [PubMed]

89.

Allard C, Morford JJ, Xu B, Salwen B, Xu W, Desmoulins L, et al. Loss of nuclear and membrane estrogen receptor-α differentially impairs insulin secretion and action in male and female mice. Diabetes. 2019;68:490–501. [DOI] [PubMed] [PMC]

90.

Kumar R, Balhuizen A, Amisten S, Lundquist I, Salehi A. Insulinotropic and antidiabetic effects of 17β-estradiol and the GPR30 agonist G-1 on human pancreatic islets. Endocrinology. 2011;152:2568–79. [DOI] [PubMed]

91.

Liu S, Kilic G, Meyers MS, Navarro G, Wang Y, Oberholzer J, et al. Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes. Diabetologia. 2013;56:370–81. [DOI] [PubMed] [PMC]

92.

Bian C, Bai B, Gao Q, Li S, Zhao Y. 17β-estradiol regulates glucose metabolism and insulin secretion in rat islet β cells through GPER and Akt/mTOR/GLUT2 pathway. Front Endocrinol. 2019;10:531. [DOI] [PubMed] [PMC]

93.

Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295:1288–99. [DOI] [PubMed]

94.

Schiffer L, Kempegowda P, Arlt W, O’Reilly MW. Mechanisms in endocrinology: the sexually dimorphic role of androgens in human metabolic disease. Eur J Endocrinol. 2017;177:R125–43. [DOI] [PubMed] [PMC]

95.

Xu W, Morford J, Mauvais-Jarvis F. Emerging role of testosterone in pancreatic β-cell function and insulin secretion. J Endocrinol. 2019;240:R97–105. [DOI]

96.

Fernández-Pérez L, de Mirecki-Garrido M, Recio C, Guerra B. Control of liver gene expression by sex steroids and growth hormone interplay. In: Salvador JAR, Silva MMC, editor. Chemistry and biological activity of steroids. London: IntechOpen; 2019. [DOI]

97.

Ji S, Guan R, Frank SJ, Messina JL. Insulin inhibits growth hormone signaling via the growth hormone receptor/JAK2/STAT5B Pathway. J Biol Chem. 1999;274:13434–42. [DOI] [PubMed]

98.

Chhabra Y, Nelson CN, Plescher M, Barclay JL, Smith AG, Andrikopoulos S, et al. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity. FASEB J. 2019;33:6412–30. [DOI] [PubMed] [PMC]

99.

Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg. 2015;109:9–15. [DOI] [PubMed] [PMC]

100.

Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–7. [DOI] [PubMed]

101.

González F. Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids. 2012;77:300–5. [DOI] [PubMed] [PMC]

102.

González F, Rote NS, Minium J, Kirwan JP. Increased activation of nuclear factor κB triggers inflammation and insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:1508–12. [DOI] [PubMed]

103.

Chen MJ, Chen HF, Chen SU, Ho HN, Yang YS, Yang WS. The relationship between follistatin and chronic low-grade inflammation in women with polycystic ovary syndrome. Fertil Steril. 2009;92:2041–4. [DOI] [PubMed]

104.

Yang JH, Chou CH, Yang WS, Ho HN, Yang YS, Chen MJ. Iron stores and obesity are negatively associated with ovarian volume and anti-Müllerian hormone levels in women with polycystic ovary syndrome. Taiwan J Obstet Gynecol. 2015;54:686–92. [DOI] [PubMed]

105.

Adolph TE, Grander C, Grabherr F, Tilg H. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Int J Mol Sci. 2017;18:E1649. [DOI] [PubMed] [PMC]

106.

Frank A, Brown LM, Clegg DJ. The role of hypothalamic estrogen receptors in metabolic regulation. Front Neuroendocrinol. 2014;35:550–7. [DOI] [PubMed] [PMC]

107.

Böttner A, Kratzsch J, Müller G, Kapellen TM, Blüher S, Keller E, et al. Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab. 2004;89:4053–61. [DOI] [PubMed]

108.

Bloomer SA, Wellen KE, Henderson GC. Sexual dimorphism in the hepatic protein response to a moderate trans fat diet in senescence-accelerated mice. Lipids Health Dis. 2017;16:243. [DOI] [PubMed] [PMC]

109.

Santolla MF, Lappano R, De Marco P, Pupo M, Vivacqua A, Sisci D, et al. G protein-coupled estrogen receptor mediates the up-regulation of fatty acid synthase induced by 17β-estradiol in cancer cells and cancer-associated fibroblasts. J Biol Chem. 2012;287:43234–45. [DOI] [PubMed] [PMC]

110.

Katz N, Thiele J, Giffhorn-Katz S. Zonal distribution of fatty acid synthase in liver parenchyma of male and female rats. Eur J Biochem. 1989;180:185–9. [DOI] [PubMed]

111.

Pearce J, Balnave D. The effects of estradiol administration of the hepatic activities of some enzymes of carbohydrate, amino acid and lipid metabolism in the immature pullet. Horm Metab Res. 1976;8:181–3. [DOI] [PubMed]

112.

McCoin CS, Von Schulze A, Allen J, Fuller KNZ, Xia Q, Koestler DC, et al. Sex modulates hepatic mitochondrial adaptations to high-fat diet and physical activity. Am J Physiol Endocrinol Metab. 2019;317:E298–311. [DOI] [PubMed] [PMC]

113.

Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001;413:179–83. [DOI] [PubMed]

114.

Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90. [DOI] [PubMed] [PMC]

115.

Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, et al. PGC-1β in the regulation of hepatic glucose and energy metabolism. J Biol Chem. 2003;278:30843–8. [DOI] [PubMed]

116.

Chambers KT, Chen Z, Crawford PA, Fu X, Burgess SC, Lai L, et al. Liver-specific PGC-1beta deficiency leads to impaired mitochondrial function and lipogenic response to fasting-refeeding. PLoS One. 2012;7:e52645. [DOI] [PubMed] [PMC]

117.

Besse-Patin A, Léveillé M, Oropeza D, Nguyen BN, Prat A, Estall JL. Estrogen signals through peroxisome proliferator-activated receptor-γ coactivator 1α to reduce oxidative damage associated with diet-induced fatty liver disease. Gastroenterology. 2017;152:243–56. [DOI] [PubMed]

118.

Galmés-Pascual BM, Nadal-Casellas A, Bauza-Thorbrügge M, Sbert-Roig M, García-Palmer FJ, Proenza AM, et al. 17β-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B. J Endocrinol. 2017;232:297–308. [DOI] [PubMed]

119.

Du K, Williams CD, McGill MR, Jaeschke H. Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol. 2014;281:58–66. [DOI] [PubMed] [PMC]

120.

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61. [DOI] [PubMed]

121.

Hampton RY. ER stress response: getting the UPR hand on misfolded proteins. Curr Biol. 2000;10:R518–21. [DOI] [PubMed]

122.

Rossetti CL, de Oliveira Costa HM, Barthem CS, da Silva MH, de Carvalho DP, da-Silva WS. Sexual dimorphism of liver endoplasmic reticulum stress susceptibility in prepubertal rats and the effect of sex steroid supplementation. Exp Physiol. 2019;104:677–90. [DOI] [PubMed]

123.

Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, et al. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes. 2016;7:313–22. [DOI] [PubMed] [PMC]

124.

de la Cuesta-Zuluaga J, Kelley ST, Chen Y, Escobar JS, Mueller NT, Ley RE, et al. Age- and sex-dependent patterns of gut microbial diversity in human adults. mSystems. 2019;4:e00261–19. [DOI]

125.

Liu HX, Keane R, Sheng L, Wan YJ. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015;63:1502–10. [DOI] [PubMed] [PMC]

126.

127.

Tobari M, Hashimoto E. Characteristic features of nonalcoholic fatty liver disease in Japan with a focus on the roles of age, sex and body mass index. Gut Liver. 2020;[Epub ahead of print]. [DOI]

128.

Marin V, Rosso N, Dal Ben M, Raseni A, Boschelle M, Degrassi C, et al. An animal model for the juvenile non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. PLoS One. 2016;11:e0158817. [DOI] [PubMed] [PMC]

129.

Ma X, Zhou Y, Qiao B, Jiang S, Shen Q, Han Y, et al. Androgen aggravates liver fibrosis by activation of NLRP3 inflammasome in CCl₄ induced liver injury mouse model. Am J Physiol Endocrinol Metab. 2020;[Epub ahead of print]. [DOI]

130.

Neamatallah T, Abdel-Naim AB, Eid BG, Hasan A. 2-Methoxyestradiol attenuates liver fibrosis in mice: implications for M2 macrophages. Naunyn Schmiedebergs Arch Pharmacol. 2019;392:381–91. [DOI] [PubMed]

131.

Kurt Z, Barrere-Cain R, LaGuardia J, Mehrabian M, Pan C, Hui ST, et al. Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ. 2018;9:46. [DOI] [PubMed] [PMC]

132.

Cvitanović Tomaš T, Urlep Ž, Moškon M, Mraz M, Rozman D. LiverSex computational model: sexual aspects in hepatic metabolism and abnormalities. Front Physiol. 2018;9:360. [DOI] [PubMed] [PMC]

133.

Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology. 2014;146:46–62. [DOI] [PubMed]

134.

Mittelstrass K, Ried JS, Yu Z, Krumsiek J, Gieger C, Prehn C, et al. Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet. 2011;7:e1002215. [DOI] [PubMed] [PMC]

135.

Saito K, Maekawa K, Kinchen JM, Tanaka R, Kumagai Y, Saito Y. Gender- and age-associated differences in serum metabolite profiles among Japanese populations. Biol Pharm Bull. 2016;39:1179–86. [DOI] [PubMed]

136.

Krumsiek J, Mittelstrass K, Do KT, Stückler F, Ried J, Adamski J, et al. Gender-specific pathway differences in the human serum metabolome. Metabolomics 2015;11:1815–33. [DOI] [PubMed] [PMC]

137.

Li Z, Zhang Y, Hu T, Likhodii S, Sun G, Zhai G, et al. Differential metabolomics analysis allows characterization of diversity of metabolite networks between males and females. PLoS One. 2018;13:e0207775. [DOI] [PubMed] [PMC]

138.

Meda C, Barone M, Mitro N, Lolli F, Pedretti S, Caruso D, et al. Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids. Mol Metab. 2020;32:97–108. [DOI] [PubMed] [PMC]

139.

Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH, et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005;69:928–33. [DOI] [PubMed]

140.

Lonardo A, Loria P, Leonardi F, Borsatti A, Neri P, Pulvirenti M, et al. Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study. Dig Liver Dis. 2002;34:204–11. [DOI] [PubMed]

141.

Xu C, Yu C, Xu L, Miao M, Li Y. High serum uric acid increases the risk for nonalcoholic fatty liver disease: a prospective observational study. PLoS One. 2010;5:e11578. [DOI] [PubMed] [PMC]

142.

Albrecht E, Waldenberger M, Krumsiek J, Evans AM, Jeratsch U, Breier M, et al. Metabolite profiling reveals new insights into the regulation of serum urate in humans. Metabolomics. 2014;10:141–51. [DOI] [PubMed] [PMC]

143.

Darmawan G, Hamijoyo L, Hasan I. Association between serum uric acid and non-alcoholic fatty liver disease: a meta-analysis. Acta Med Indones. 2017;49:136–47. [PubMed]

144.

Liu Z, Que S, Zhou L, Zheng S. Dose-response relationship of serum uric acid with metabolic syndrome and non-alcoholic fatty liver disease incidence: a meta-analysis of prospective studies. Sci Rep. 2015;5:14325. [DOI] [PubMed] [PMC]

145.

Wu SJ, Zhu GQ, Ye BZ, Kong FQ, Zheng ZX, Zou H, et al. Association between sex-specific serum uric acid and non-alcoholic fatty liver disease in Chinese adults: a large population-based study. Medicine (Baltimore). 2015;94:e802. [DOI] [PubMed] [PMC]

146.

Yang H, Li D, Song X, Liu F, Wang X, Ma Q, et al. Joint associations of serum uric acid and ALT with NAFLD in elderly men and women: a Chinese cross-sectional study. J Transl Med. 2018;16:285. [DOI] [PubMed] [PMC]

147.

Gurian E, Giraudi P, Rosso N, Tiribelli C, Bonazza D, Zanconati F, et al. Differentiation between stages of non-alcoholic fatty liver diseases using surface-enhanced Raman spectroscopy. Anal Chim Acta. 2020;1110:190–8. [DOI] [PubMed]

148.

Culafic M, Vezmar Kovacevic S, Dopsaj V, Stulic M, Vlaisavljevic Z, Miljkovic B, et al. A simple index for nonalcoholic steatohepatitis—HUFA—based on routinely performed blood tests. Medicina. 2019;55:E243. [DOI] [PubMed] [PMC]

149.

Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate. Hepatol Res. 2016;46:1074–87. [DOI] [PubMed]

150.

Sandra S, Lesmana CRA, Purnamasari D, Kurniawan J, Gani RA. Hyperuricemia as an independent risk factor for non-alcoholic fatty liver disease (NAFLD) progression evaluated using controlled attenuation parameter-transient elastography: lesson learnt from tertiary referral center. Diabetes Metab Syndr. 2019;13:424–8. [DOI] [PubMed]

151.

Huang JF, Yeh ML, Huang CF, Huang CI, Tsai PC, Tai CM, et al. Cytokeratin-18 and uric acid predicts disease severity in Taiwanese nonalcoholic steatohepatitis patients. PLoS One. 2017;12:e0174394. [DOI] [PubMed] [PMC]

152.

Jaruvongvanich V, Ahuja W, Wijarnpreecha K, Ungprasert P. Hyperuricemia is not associated with severity of liver fibrosis in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017;29:694–7. [DOI] [PubMed]

153.

Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184–96. [DOI] [PubMed]

154.

Anfuso B, Tiribelli C, Adorini L, Rosso N. Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model. Sci Rep. 2020;10:1699. [DOI] [PubMed] [PMC]

155.

Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology. 2020;71:1198–212. [DOI] [PubMed]

156.

Ritchie M, Hanouneh IA, Noureddin M, Rolph T, Alkhouri N. Fibroblast growth factor (FGF)-21 based therapies: a magic bullet for nonalcoholic fatty liver disease (NAFLD)? Expert Opin Investig Drugs. 2020;29:197–204. [DOI]

157.

Van Meeteren MJW, Drenth JPH, Tjwa ETTL. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:117–23. [DOI]