Down-regulation of the LXR transcriptome provides the requisite cholesterol levels to proliferating hepatocytes

Abstract

Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) ␣ and ␤ are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. Here we employed a mouse model of partial hepatectomy (PH) to dissect the molecular pathways connecting cholesterol homeostasis, cellular proliferation, and LXR. First, we show that hepatic cholesterol content increases after PH, whereas the entire LXR transcriptome is down-regulated. Although LXR messenger RNA (mRNA) levels are unmodified, LXR target genes are significantly down-regulated on day 1 after PH and restored to control levels on day 7, when the liver reaches normal size. The inactivation of LXR following PH is related to the reduced oxysterol availability by way of decreased synthesis, and increased sulfation and secretion. On the contrary, cholesterol synthesis is up-regulated, and extracellular matrix remodeling is enhanced. Second, we show that reactivation of LXR by way of a synthetic ligand determines a negative modulation of hepatocyte proliferation. This effect is sustained by the reactivation of hepatic cholesterol catabolic and secretory pathways, coupled with a significant reduction of cholesterol biosynthesis. Our data unveil a previously unrecognized and apparently paradoxical scenario of LXR modulation. During liver regeneration LXR activity is abated in spite of increasing intracellular cholesterol levels. Turning off LXR-transcriptional pathways is crucial to guaranteeing the requisite intracellular cholesterol levels of regenerating hepatocytes. In line with this hypothesis, pharmacological LXR reactivation during PH significantly reduces liver regeneration capacity. (HEPATOLOGY 2010;51:1334-1344 C holesterol is not only the precursor of steroid hormones but also a regulator of embryonic development and cell proliferation, being a key component of the cell membrane. 1,2 Thus, there is a need of coordinate tuning of cholesterol metabolism and lipogenic gene expression during membrane synthesis, cellular differentiation, and proliferation. Proliferating cells satisfy their cholesterol demand by increasing their uptake of exogenous cholesterol 3 through an increase in low-density lipoprotein receptor. 4 When cholesterol synthesis is inhibited by HMG-CoA reductase inhibitor, cell growth is reduced, 5 whereas the subsequent addition of choles-

Cross-talk between the Androgen Receptor and the Liver X Receptor

“…Cholesterol-independent mechanisms have also been proposed (59), such as influencing G 1 -S transition via Skp (56). The antiproliferative effect of LXR has also been described outside the cancerous setting, in the regenerating liver, whereby LXR lowers cholesterol required for hepatocyte proliferation (60).…”

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

“…Liver proliferation is an energy and material-consuming process that causes a dramatic consuming of both TG and cholesterol from serum and liver in a short time (15). Although the detailed lipid regulatory pathway is still unclear, lots of studies have reached a consensus on the lipid metabolic characteristics during this process (15)(16)(17)(18)(19). It enhanced fatty acid oxidation in liver for energy production, and upregulated both hepatic cholesterol synthesis and uptake for cell membrane synthesis (15,16).…”

“…Although the detailed lipid regulatory pathway is still unclear, lots of studies have reached a consensus on the lipid metabolic characteristics during this process (15)(16)(17)(18)(19). It enhanced fatty acid oxidation in liver for energy production, and upregulated both hepatic cholesterol synthesis and uptake for cell membrane synthesis (15,16). The increased fatty acid oxidation in liver ameliorates the hepatic steatosis, and decreases the VLDL secretion to lower serum TG (17).…”

“…Meanwhile, the upregulated hepatic cholesterol uptake dramatically lowers serum total cholesterol (TC) (18). Especially when serum cholesterol is high, the cholesterol uptake from serum may become a more important source in comparison with the hepatic cholesterol synthesis (18), which is not induced until preexisting cholesterol has become insufficient to meet the cellular demand (16). Collectively, these studies suggested that complement system might be involved in lipid metabolism regulation via liver proliferation, and liver proliferation might be a potential high-efficiency treatment strategy with a very short treatment cycle against NAFLD, hypertriglyceridemia and hypercholesteremia.…”

Metabolic demand of the hepatic cell cycle

“…The role of lipids, both cholesterol and triglycerides (TG), in the regenerating liver following PH is believed to be critical. 1,2 Yet, the precise role of lipids in liver regeneration have yielded somewhat diverging results. Specifically, dietinduced fat accumulation in liver using western or high fat diet resulted in impaired liver regeneration, 3 while suppression of hepatocyte-derived fat accumulation resulted in impaired proliferation of the liver following PH.…”