Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation‐related protein (ADRP)

Abstract

Hepatic stellate cells (HSCs) store retinoids and triacylglycerols in cytoplasmic lipid droplets. Two prominent features of HSC activation in liver fibrosis are loss of lipid droplets along with increase of α-smooth muscle actin (α-SMA), but the link between these responses and HSC activation remains elusive. In non-adipose cells, adipose differentiation-related protein (ADRP) coats lipid droplets and regulates their formation and lipolysis; however its function in HSCs is unknown. Here, we observed, in human liver sections or primary HSC culture, ADRP localization to lipid droplets of HSCs, and reduced staining coincident with loss of lipid droplets in liver fibrosis and in culture-activated HSCs, consistent with HSC activation. In the LX-2 human immortalized HSCs, with scant lipid droplets and features of activated HSCs, we found that the upregulation of ADRP mRNA by palmitate is potentiated by retinol, accompanied by increased ADRP protein, generation of retinyl palmitate and lipid droplet formation. ADRP induction also led to decreased expression of α-SMA mRNA and its protein, while ADRP knockdown with small interfering RNA (siRNA) normalized α-SMA expression. Furthermore, ADRP induction by retinol and palmitate resulted in decreased expression of collagen I and matrix metalloproteinase-2 mRNA, fibrogenic genes associated with activated HSCs, while increasing matrix metalloproteinase-1 mRNA; ADRP knockdown with siRNA reversed these changes. Tissue inhibitor of metalloproteinase-1 was not affected. Thus, ADRP upregulation mediated by retinol and palmitate promotes downregulation of HSC activation and is functionally linked to the expression of fibrogenic genes.

Intraperitoneal application of phospholipids for the prevention of postoperative adhesions: a possible role of myofibroblasts

“…In addition to the mixture of phospholipids (their composition is reported in the Materials and Methods section), Vitalipid also contains triglycerides and fat soluble vitamins A, D, E, and K. With the exception of vitamin E, fat soluble vitamins have never been investigated for the prevention of postoperative adhesions. There are experimental data that suggest a possible antifibrotic effect for vitamins A and D. Previous studies indicate that vitamin A may have a beneficial role in liver fibrosis through inhibition of the activation and/or proliferation of hepatic stellate cells and via the downregulation of collagen production [42,43]. Signaling through the vitamin D receptor antagonizes the effects of TGFb possibly through direct interaction with SMAD3 and attenuates experimental renal, skin, myocardial, and liver fibrosis [44e49].…”

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

“…3D). LDs are characteristic of resident HSCs and their presence and induction suppress HSCs activation 33, 34. Autophagy contributes to the intracellular catabolism of lipids in HSCs 8.…”

Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes

“…ADRP is expressed at a strong level in normal human liver with a drastic decrease in expression in the lipid-poor HSCs activated cells found in fibrotic liver. More recently, results from Lee et al [31] showed that down-regulation of HSC activation in LX-2 cells, by a synergistic combination of retinol and palmitic acid, is mediated by ADRP and is strongly linked to the expression of the fibrogenic genes. We already know that fatty acids are able to activate the expression of ADRP in non lipid cells or the other PAT proteins in adipocytes.…”