Basic—Liver, Pancreas, and Biliary TractLiver X Receptor Signaling Is a Determinant of Stellate Cell Activation and Susceptibility to Fibrotic Liver Disease
Section snippets
Mice and Liver Injury Models
Male Lxrαβ−/− mice (12–24 weeks old) were obtained by backcrossing ≥10 generations on a pure C57/Bl6 background. Animal housing was temperature controlled with a 12-hour light/dark cycle, pathogen-free conditions, and ad libitum access to water and standard chow. The following specialized diets (Research Diets, New Brunswick, NJ) were used (see Figure 6): control diet, A02082003B; methionine/choline-deficient (MCD) diet, A02082002B. These diets differ only in the presence or absence of dl
LXRs Have Reciprocal Anti-inflammatory and Lipid Metabolic Effects in Activated Stellate Cells
To characterize nuclear receptor expression in hepatic stellate cells, we performed quantitative real-time polymerase chain reaction on 2 immortalized, fully activated stellate cell lines: rat HSC-T6 cells24 and human LX-2 cells.25 These lines are supposed to model stellate cells in their fully activated, myofibroblast-like state. Supplementary Table 1 lists the relative abundance of RXR heterodimers found in LX-2 cells, with LXRβ, vitamin D, thyroid, retinoic acid (RARα), and retinoid X (RXRα)
Discussion
LXRs are key regulators of cholesterol homeostasis and hepatic lipogenesis,16 but they also transrepress inflammatory genes in macrophages17 and mediate antiproliferative effects in T cells during the adaptive immune response.20 We have shown here that LXRs are among the most highly expressed nuclear receptors in stellate cells and that LXR signaling regulates the expression of genes linked to metabolism, inflammation, and fibrogenesis in primary cells. Consistent with the ability of LXRs to
Acknowledgments
The authors thank David Mangelsdorf for LXR-null mice, Tim Willson for GW3965, Scott Friedman for the HSC-T6 and LX-2 cell lines, Sam French Sr for assistance with α–smooth muscle actin immunohistochemistry, Clara Magyar for digital quantification of fibrosis, and Jon Salazar for assistance with mouse husbandry.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health training grant T32 DK07180-30, UCLA Center for Ulcer Research and Education (CURE) Pilot and Feasibility Study grant 441349-BB-39108 (to S.W.B.), and grants HL66088, HL30568, and DK063491 (to P.T.). Additional support for cell isolation (H.T.) was from R24AA12885 (Non-Parenchymal Liver Cell Core) and P50AA11999 (Southern California Research Center for ALPD & Cirrhosis). P.T. is an investigator of the Howard Hughes Medical Institute.