Hepatic metabolism and gender

Adriana Maggi, Sara Della Torre

Centre of Excellence on Neurodegenerative Diseases, Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy

Our past studies demonstrated a major transcriptional activity of the estrogen receptor alpha (ER) in the liver1; such transcriptional activity is tightly regulated by the circulating levels of estradiol and by alimentary cues2,3. Further studies pointed to the liver as a sensor of the state of nutrition possibly necessary to inhibit reproductive functions in the case of famine3. Indeed, all through phylogenesis there is a major connection between reproductive and metabolic functions; the indissoluble association between the liver and the female gonads is due to the fact that most proteins indispensable for ovulation are of hepatic origin and their synthesis occur upon stimulation by estradiol, a sex steroid synthesized in the ovaries. This is very well established for oviparous species and less studied in mammals. Our finding of a strict association between gonadal functions and ER transcriptional activity in the liver has led us to further investigate the hepatic genes modulated by this receptor in the course of the reproductive cycle. We found that in female mice ER has a major role in the regulation of lipid metabolism and transport, that appears to be adapted to the state of reproduction: lipids synthesis is negatively regulated by estrogens and changes depending of the phase of the cycle and on the state of fertility4,5; these observations led us to hypothesize that with the advent of placentation and the changes in reproductive strategies occurring in mammals, the female liver had to adjust to the significant changes in energy demands associated with ovulation, pregnancy and lactation and adopt mechanisms of tight control over the hepatic energy metabolism, thus determining a major divergence from the original functions that, conceivably, were the most similar in the two sexes6,7. To test this hypothesis, we carried out a series of transcriptomics and metabolomics analyses of the livers of adult males and females and identified major differences in the strategies utilized with regard to the response to metabolic stress. In fertile animals the female liver proved to be much more parsimonious than the male liver in the exploitation of alimentary molecules and very cautious in the generation of storage energy molecules, limiting any waste of molecules that could be precious in sustaining ovulation and pregnancy8. These changes in the liver metabolic strategies may explain the different susceptibility to liver and liver-associated pathologies in the two sexes and the increased incidence of these pathologies in women at the end of their reproductive cycle.

Thus these studies, underlying profound sex differences in major metabolic organ, demand further analyses with humans because they might establish the bases for novel strategies for sex-specific treatments of metabolic disorders.




Acknowledgements

This work was supported by a grant from the European Community (ERC-Advanced Grant 322977, WAYS) and by the Seventh Framework program under the grant agreement n° 278850 (INMIND).

References

1. Ciana P, Raviscioni M, Vegeto E, Mussi P, Que I, Parker M, Lowik C, Maggi A. In vivo imaging of transcriptionally active estrogen receptor. Nature Medicine 2003; 9: 82-6.

2. Ciana P, Brena A, Sparaciari P, Bonetti E, Di Lorenzo D, Maggi A. Estrogenicactivities in rodentestrogen-free diets. Endocrinology 2005; 2: 5144-50.

3. Della Torre S, Rando G, Meda C, Stell A, Chambon P, Ktust A, Ibarra C, Magni P, Ciana P, Maggi A. Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. Cell Metabolism 2011; 13: 205-14.

4. Della Torre S, Mitro N, Fontana R, Gomaraschi M, Favari E, Maggi A. An essential role for liver erα in coupling hepatic metabolism to the reproductive cycle. Cell Rep 2016; 15: 360-71.

5. Villa A, Della Torre S, 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 USA 2012; 109: 11806-11.

6. Della Torre S, Maggi A. Sex difference: a resultant of evolutionary pressure? Cell Metabolism 2017; 25: 499-501.

7. Della Torre S, Benedusi V, Fontana R and Maggi A. Energy metabolism and fertility a balance preserved for female health. Nat Rev Endocrinol 2014; 10: 13-23.

8. Della Torre S, Mitro N, MedA C, Lolli F, Pedretti S, Barcella M, Ottobrini L, Metzger D, Caruso D, Maggi A. Short-term fasting reveals AA metabolism as a sex determining factor in the liver. Cell Metabolism, under revision.

Correspondence to

Adriana Maggi

Director Center of Excellence on Neurodegenerative Diseases

University of Milan

Via Balzaretti 9

20133 Milan, Italy

email adriana.maggi@unimi.it