Pregnancy and weaning regulate human maternal liver size and function

Abstract

BACKGROUND: During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a pro-metastatic niche. These data suggest a mechanism for increased liver metastasis in postpartum breast cancer patients. OBJECTIVES: Investigate if the human liver changes in size and function during pregnancy and weaning. METHODS: Abdominal imaging was obtained in healthy women at early and late pregnancy, and post-wean. During pregnancy time points, endogenous glucose production was measured and fasting blood taken to measure bile acids. RESULTS: Independent of weight gain, most women's livers increased in size with pregnancy, returning to baseline post-wean. Putative roles for bile acids in liver growth were observed in pregnant women and rodents. CONCLUSIONS: The human liver is regulated by reproductive state with growth during pregnancy and volume loss post-wean. These findings may have broad implications for sexspecific liver diseases and cancer.

Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model

“…The suppression in vitamin D metabolism we observed in the post-wean period is likely a direct consequence of weaning-induced liver involution, which we recently reported in rodents (50–52). Relevance to women is suggested, as the human liver also undergoes volume gain with pregnancy followed by post-wean volume loss, consistent with weaning-induced liver involution (52). In mice, liver involution establishes a metastatic niche (50, 51), which may account for increased liver metastasis observed in postpartum breast cancer patients (3, 6, 7).…”

“…The suppression in vitamin D metabolism we observed in the post-wean period is likely a direct consequence of weaning-induced liver involution, which we recently reported in rodents (50)(51)(52).…”

“…Relevance to women is suggested, as the human liver also undergoes volume gain with pregnancy followed by post-wean volume loss, consistent with weaning-induced liver involution (52). In mice, liver involution establishes a metastatic niche (50,51), which may account for increased liver metastasis observed in postpartum breast cancer patients (3,6,7).…”

“…Quantitative PCR Livers were collected from mice at the following reproductive stages: nulliparous (n=4), involution day 2 (n=3) and involution day 4 (n=4). RNA was isolated from livers, as described in (52). Total cDNA was reverse transcribed from 500ng of RNA using iScript IV VILO cDNA synthesis kit (Bio-Rad), with reactions incubated at 25°C for 5 min, 42°C for 25 min, and 85°C for 5 min.…”

Vitamin D as a Potential Preventive Agent For Young Women's Breast Cancer

“…Critically, the rodent involuting liver also exhibits metabolic signatures of protein catabolism and oxidative stress. In postpartum women, indirect evidence of liver involution comes from a recent study which demonstrates that liver size increases with pregnancy, before returning to normal size post-wean (140). As the liver is a primary site of vitamin D synthesis, it is possible that during weaning-induced involution the liver is compromised in its ability to hydroxylase vitamin D. Albeit an untested hypothesis, this could result in reduced circulating concentrations of 25(OH)D during involution; a hallmark of vitamin D deficiency.…”