Hepatocyte-macrophage shuttle protects against liver fibrosis

Hepatocyte-macrophage shuttle protects against live fibrosis


Researchers have made a discovery which could lead to a new way of thinking about how disease pathogenesis in the liver is regulated, which is important for understanding the condition nonalcoholic fatty liver disease (NAFLD), which is incredibly common and growing. It is apparent that about 30 percent of Americans and are at risk to advance to more severe conditions such as nonalcoholic steatohepatitis (NASH), cirrhosis, cardiovascular disease, or even liver cancer.

In a recently published article in Cell Metabolism, authors found that a metabolite shuttle, or dialogue, between hepatocyte and macrophage cell types in the liver helps protect against tissue fibrosis.

Authors shoe that in both classically and alternatively polarized macrophages, [ 13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[ 13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [ 13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT).

AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. 

"We found that when a dialogue involving a specific ketone body metabolite is prevented experimentally, the liver is predisposed to a more severe form of NAFLD that includes scarring. Giving experimental animals this specific ketone body can protect the liver from scarring," said the senior author.

Ketone bodies are considered alternative fuels to carbohydrates or fats, and have been studied for decades, but the fundamental aspect of specificity and discrimination of how specific ketone bodies are selectively burned, and that this specificity could influence liver health, had never been known before. Another key discovery is that a metabolic dialogue between two closely residing cell type neighbors within the liver even existed.

"I hope people now look differently at ketone bodies," said the author. "Usually people look at them only as an alternative energy source to sugars, and we could see for the first time that different ketone bodies have quite differential roles."


https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30647-8

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