• What Controls Liver Size?

What Controls Liver Size?

Most people know that liver can regenerate, but how does it know when to stop growing? Liver size is, in part, regulated by the size of the circulating bile acid pool, controlled by fibroblast growth factor 19 (FGF19), researchers show in the September issue of Gastroenterology.

The mammalian liver can regrow after injury. Following partial hepatectomy, the remnant liver grows back to within 5% of the original size within 7−10 days in rodents and 4−8 weeks in humans. The liver mass regained is proportional to body size. Although some molecular signals have been found to control liver size, liver-to-body weight ratio likely also depends on some of the liver’s functions.

Bile acids regulate liver regeneration and might also help determine liver size. Bile acid synthesis is regulated by cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1)—this endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway in the liver, which converts cholesterol to bile acids.

Expression of CYP7A1 is down-regulated by of FGF19 (in mice, FGF15), produced in the intestine.

Livers of FRGN mice can be destroyed and then fully repopulated with human hepatocytes. Interestingly, these humanized livers grow to a larger size than the original mouse liver. The humanized livers also express higher levels of CYP7A. This is because the human liver cells do not recognize the mouse FGF15—they only respond to the human form, FGF19.  The high expression of CYP7A1 in the humanized livers leads to high production of bile acids.

Willscott E. Naugler et al investigated whether FGF19 regulation of CYP7A1 and bile acid production control liver size in FRGN mice

They inserted the gene encoding human FGF19, including its regulatory sequences, into the FRGN mice to create FRGN19+ mice. Livers of FRGN19+ mice and their FRGN littermates were then fully repopulated with human hepatocytes.

As previously observed, livers were larger in FRGN mice with humanized livers (13% of body weight), compared with control FRGN mice, due to increased hepatocyte proliferation; FRGN mice with humanized livers also had much larger bile acid pools and aberrant bile acid signaling. However, livers from FRGN19+ were normalized, to 7.8% of body weight; their bile acid pool and signaling more closely resembled that of control mice.

The authors concluded that FGF19 intestine–liver signaling controls bile acid homeostasis and liver size.

RNA sequence analyses of the enlarged, humanized livers of FRGN mice showed activation of the Hippo pathway, which regulates the size of liver and other organs. The forkhead box M1 (FOXM1) pathway was also significantly up-regulated in these livers. FOXM1 expression is regulated by the farnesoid X receptor—its increased expression promotes hepatocyte proliferation.

What tissues produce FGF19 in humans? The authors found that heathy human liver tissues expressed almost no FGF19 RNA, but nonparenchymal cells in liver tissues from patients with cirrhosis due to hepatitis C virus infection or biliary cirrhosis had increased expression of FGF19 RNA. The FGF19-expressing mice with humanized livers produced by Naugler et al might therefore be a useful model for studying human cholestatic diseases.

In an editorial that accompanies the article, Matias A. Avila and Antonio Moschetta state that these findings provide support for the hypothesis that liver growth is regulated by the size of the bile acid pool.

(A) Aberrant signaling perturbs bile acid homeostasis when transplanted human hepatocytes fail to recognize Fgf15, the mouse intestinal signal for inhibiting bile acid synthesis in the liver. This leads to an enlarged bile acid pool and an increase in the hepatocyte mass needed to circulate the pool. (B) Expression of FGF19 allows transplanted human hepatocytes to properly regulate bile acid synthesis and normalize the bile acid pool. Hepatocytes are reduced in proportional to the bile acid pool to be circulated.

(A) Transplanted human hepatocytes do not recognize FGF15, the mouse intestinal signal that downregulates CYP7A1 and reduces bile acid synthesis. This leads to a larger bile acid pool and an increase in the number of hepatocytes needed to circulate the pool. (B) Expression of FGF19 allows transplanted human hepatocytes to downregulate CYP7A1 and thereby reduces bile acid synthesis, to normalize the bile acid pool. Hepatocytes are reduced in proportion to the bile acid pool.

How does bile acid control liver size? Naugler et al explain that the continually circulating bile acid pool is relatively fixed in size and proportional to the size of the organism (in mice and rats it is 13 μmol/g liver and in humans it is 50−60 mmol/kg body weight). The size of the bile acid pool is controlled in the ileum, where enterocytes reabsorb bile acids and provide negative feedback for bile acid synthesis in the liver, via production of FGF15 (in rodents) or FGF19 (in humans).

Naugler et al propose a model (see figure) in which liver growth occurs when the bile acid pool exceeds the liver’s maximum secretory capacity.

Avila and Moschetta say it will be interesting to test the effects of reducing the bile acid pool in FRGN mice with humanized livers by other methods, such as feeding the mice a bile acid-sequestering resin.

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