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Hepatic stellate cells are an important cellular site for ?-carotene conversion to retinoid.

ABSTRACT: Hepatic stellate cells (HSCs) are responsible for storing 90-95% of the retinoid present in the liver. These cells have been reported in the literature also to accumulate dietary ?-carotene, but the ability of HSCs to metabolize ?-carotene in situ has not been explored. To gain understanding of this, we investigated whether ?-carotene-15,15'-monooxygenase (Bcmo1) and ?-carotene-9',10'-monooxygenase (Bcmo2) are expressed in HSCs. Using primary HSCs and hepatocytes purified from wild type and Bcmo1-deficient mice, we establish that Bcmo1 is highly expressed in HSCs; whereas Bcmo2 is expressed primarily in hepatocytes. We also confirmed that HSCs are an important cellular site within the liver for accumulation of dietary ?-carotene. Bcmo2 expression was found to be significantly elevated for livers and hepatocytes isolated from Bcmo1-deficient compared to wild type mice. This elevation in Bcmo2 expression was accompanied by a statistically significant increase in hepatic apo-12'-carotenal levels of Bcmo1-deficient mice. Although apo-10'-carotenal, like apo-12'-carotenal, was readily detectable in livers and serum from both wild type and Bcmo1-deficient mice, we were unable to detect either apo-8'- or apo-14'-carotenals in livers or serum from the two strains. We further observed that hepatic triglyceride levels were significantly elevated in livers of Bcmo1-deficient mice fed a ?-carotene-containing diet compared to mice receiving no ?-carotene. Collectively, our data establish that HSCs are an important cellular site for ?-carotene accumulation and metabolism within the liver.

SUBMITTER: Shmarakov I

PROVIDER: S-EPMC3692274 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Hepatic stellate cells are an important cellular site for β-carotene conversion to retinoid.

Shmarakov Igor I Fleshman Matthew K MK D'Ambrosio Diana N DN Piantedosi Roseann R Riedl Ken M KM Schwartz Steven J SJ Curley Robert W RW von Lintig Johannes J Rubin Lewis P LP Harrison Earl H EH Blaner William S WS

Archives of biochemistry and biophysics 20100512 1

Hepatic stellate cells (HSCs) are responsible for storing 90-95% of the retinoid present in the liver. These cells have been reported in the literature also to accumulate dietary β-carotene, but the ability of HSCs to metabolize β-carotene in situ has not been explored. To gain understanding of this, we investigated whether β-carotene-15,15'-monooxygenase (Bcmo1) and β-carotene-9',10'-monooxygenase (Bcmo2) are expressed in HSCs. Using primary HSCs and hepatocytes purified from wild type and Bcmo ...[more]

PMID: 20470748

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Project description:Background & aimsAramchol is a fatty acid-bile acid conjugate that reduces liver fat content and is being evaluated in a phase III clinical trial for non-alcoholic steatohepatitis (NASH). Aramchol attenuates NASH in mouse models and decreases steatosis by downregulating the fatty acid synthetic enzyme stearoyl CoA desaturase 1 (SCD1) in hepatocytes. Although hepatic stellate cells (HSCs) also store lipids as retinyl esters, the impact of Aramchol in this cell type is unknown.MethodsWe investigated the effects of Aramchol on a human HSC line (LX-2), primary human HSCs (phHSCs), and primary human hepatocytes (phHeps).ResultsIn LX-2 and phHSCs, 10 μM Aramchol significantly reduced SCD1 mRNA while inducing PPARG (PPARγ) mRNA, with parallel changes in the 2 proteins; ACTA2, COL1A1, β-PDGFR (bPDGFR) mRNAs were also significantly reduced in LX-2. Secretion of collagen 1 (Col1α1) was inhibited by 10 μM Aramchol. SCD1 knockdown in LX-2 cells phenocopied the effect of Aramchol by reducing fibrogenesis, and addition of Aramchol to these cells did not rescue fibrogenic gene expression. Conversely, in LX-2 overexpressing SCD1, Aramchol no longer suppressed fibrogenic gene expression. The drug also induced genes in LX-2 that promote cholesterol efflux and inhibited ACAT2, which catalyses cholesterol synthesis. In phHeps, Aramchol also reduced SCD1 and increased PPARG mRNA expression.ConclusionsAramchol downregulates SCD1 and elevates PPARG in HSCs, reducing COL1A1 and ACTA2 mRNAs and COL1A1 secretion. These data suggest a direct inhibitory effect of Aramchol in HSCs through SCD1 inhibition, as part of a broader impact on both fibrogenic genes as well as mediators of cholesterol homeostasis. These findings illustrate novel mechanisms of Aramchol activity, including potential antifibrotic activity in patients with NASH and fibrosis.Lay summaryIn this study, we have explored the potential activity of Aramchol, a drug currently in clinical trials for fatty liver disease, in blocking fibrosis, or scarring, by hepatic stellate cells, the principal collagen-producing (i.e. fibrogenic) cell type in liver injury. In both isolated human hepatic stellate cells and in a human hepatic stellate cell line, the drug suppresses the key fat-producing enzyme, stearoyl CoA desaturase 1 (SCD1), which leads to reduced expression of genes and proteins associated with hepatic fibrosis, while inducing the protective gene, PPARγ. The drug loses activity when SCD1 is already reduced by gene knockdown, reinforcing the idea that inhibition of SCD1 is a main mode of activity for Aramchol. These findings strengthen the rationale for testing Aramchol in patients with NASH.

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Hepatic stellate cells are an important cellular site for ?-carotene conversion to retinoid.

Publications

Hepatic stellate cells are an important cellular site for β-carotene conversion to retinoid.

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