Abstract

Retinoids are micronutrients that are stored as retinyl esters in the retina and hepatic stellate cells (HSCs). HSCs are key players in fibrogenesis in chronic liver diseases. The enzyme responsible for hydrolysis and release of retinyl esters from HSCs is unknown and the relationship between retinoid metabolism and liver disease remains unclear. We hypothesize that the patatin-like phospholipase domain-containing 3 (PNPLA3) protein is involved in retinol metabolism in HSCs. We tested our hypothesis both in primary human HSCs and in a human cohort of subjects with non-alcoholic fatty liver disease (N = 146). Here we show that PNPLA3 is highly expressed in human HSCs. Its expression is regulated by retinol availability and insulin, and increased PNPLA3 expression results in reduced lipid droplet content. PNPLA3 promotes extracellular release of retinol from HSCs in response to insulin. We also show that purified wild-type PNPLA3 hydrolyzes retinyl palmitate into retinol and palmitic acid. Conversely, this enzymatic activity is markedly reduced with purified PNPLA3 148M, a common mutation robustly associated with liver fibrosis and hepatocellular carcinoma development. We also find the PNPLA3 I148M genotype to be an independent (P = 0.009 in a multivariate analysis) determinant of circulating retinol-binding protein 4, a reliable proxy for retinol levels in humans. This study identifies PNPLA3 as a lipase responsible for retinyl-palmitate hydrolysis in HSCs in humans. Importantly, this indicates a potential novel link between HSCs, retinoid metabolism and PNPLA3 in determining the susceptibility to chronic liver disease.

Highlights

  • Retinoids are liposoluble micronutrients that are highly enriched in the retina and stellate cells [1,2]

  • We investigated the effect of the I148M mutation on retinol metabolism in human hepatic stellate cells (HSCs) and we tested for differences in circulating levels of retinol-binding protein 4 (RBP4) among individuals carrying different patatin-like phospholipase domain-containing 3 (PNPLA3) I148M genotypes

  • PNPLA3 mRNA and protein expression levels were high in primary human HSCs (pHSCs) compared with hepatocytes; the levels of PNPLA3 were high in comparison with PNPLA2, the major triglyceride esterase in hepatocytes and adipocytes (Fig. 1B and C)

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Summary

Introduction

Retinoids are liposoluble micronutrients that are highly enriched in the retina and stellate cells [1,2]. Besides playing a major physiological role in vision, they are involved in the regulation of cell proliferation and differentiation [3,4]. Retinoids are used in the treatment of malignancies [4,5] and have been shown to prevent hepatocellular carcinoma [6,7]. Retinoids are absorbed in the intestine and transported in the form of retinyl esters by chylomicrons to the liver.

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