The oxysterol receptors LXR (liver X receptor)-␣ and LXR␤ are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.Type II diabetes mellitus is a prevalent metabolic disease in developed countries, with insufficient therapies for treatment and prevention (1, 2). Studies in recent years have suggested that nuclear receptors are intimately linked to the pathophysiology of diabetes. The antidiabetic thiazolidinediones have been identified as ligands of proxisome proliferator-activated receptor ␥ (PPAR␥) 1 (3, 4). Retinoid X receptor (RXR) ligands have also been shown to lower plasma glucose levels in rodent diabetic models (3-5).Originally identified as orphan members of the nuclear receptor superfamily, liver X receptors exist as two isoforms, LXR␣ and LXR␤. The two isoforms display distinct patterns of expression with LXR␣ being primarily expressed in liver, intestine, and kidney, whereas LXR␤ is expressed ubiquitously (6). Oxysterols were identified as the putative physiological ligands for the LXRs (7), and additional studies have demonstrated that these receptors act as sensors for these cholesterol metabolites and are essential components of a physiological feedback loop regulating cholesterol metabolism and transport (8). Consistent with their role in regulation of these metabolic pathways, several LXR-regulated genes involved in lipid metabolism and cholesterol transport have been identified including ABCA1, ABCG1, ABCG5, ABCG8, ApoE, CETP, Cyp7a, LPL, SREBP1c, and FAS (8 -14).As a result of the close relationship between lipid and carbohydrate metabolism, we examined the potential role LXRs may play in glucose homeostasis by using a specific LXR agonist, T0901317, (11) in rodent models of diabetes. Our findings indicated that T0901317 dose-dependently lowered plasma glucose level in both db/db and Zucker diabetic fatty (ZDF) rat models. In the fa/fa insulin-resistant rat model, T0901317 significantly improved insulin sensitivity. Examination of the liver gluconeogenesis pathway revealed dra...

Preb 1 HDL is the initial plasma acceptor of cellderived cholesterol in reverse cholesterol transport. Recently, small amphipathic peptides composed of D-amino acids have been shown to mimic apolipoprotein A-I (apoA-I) as a precursor for HDL formation. ApoA-I mimetic peptides have been proposed to stimulate the formation of preb 1 HDL and increase reverse cholesterol transport in apoE-null mice. The existence of a monoclonal antibody (MAb 55201) and a corresponding ELISA method that is selective for the detection of the preb 1 subclass of HDL provides a means of establishing a correlation between apoA-I mimetic dose and preb 1 HDL formation in human plasma. Using this preb 1 HDL ELISA, we demonstrate marked apoA-I mimetic dosedependent preb 1 HDL formation in human plasma. These results correlated with increases in band density of the plasma preb 1 HDL, when observed by Western blotting, as a function of increased apoA-I mimetic concentration. Increased preb 1 HDL formation was observed after as little as 1 min and was maximal within 1 h. Together, these data suggest that a high-throughput preb 1 HDL ELISA provides a way to quantitatively measure a key component of the reverse cholesterol transport pathway in human plasma, thus providing a possible method for the identification of apoA-I mimetic molecules.-Troutt, J.

Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism. We have explored the hypothesis that simultaneous activation of PPARalpha and LXR may lead to additive effects on HDL cholesterol elevation as well as attenuation of triglyceride accumulation. Coadministration of T0901317 and the specific PPARalpha agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy14643)] in mice led to synergistic elevation of HDL cholesterol that was primarily associated with enlarged HDL particles enriched with apoE and apoAI. Liver phospholipid transfer protein (PLTP) mRNA and plasma PLTP activity were additively elevated, suggesting a role of PLTP in the observed HDL cholesterol elevation. Moderate increases in plasma triglyceride levels induced by LXR activation was reduced, whereas the accumulation of triglyceride in the liver was not altered upon coadministration of the PPARalpha agonist. Peroxisomal fatty acid beta-oxidation in the liver was dramatically elevated upon PPARalpha activation as expected. Interestingly, activation of LXRs via T0901317 also led to a significant increase in peroxisomal fatty acid beta-oxidation. Sterol regulatory element binding protein 1c expression was dramatically up-regulated by the LXR agonist but was not changed with PPARalpha agonist treatment. Liver lipoprotein lipase expression was additively increased upon LXR agonist and PPARalpha agonist coadministration. Our studies mark the first exploration of nuclear receptor interplay on lipid homeostasis in vivo.

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by b-catenin knockdown increased glucocorticoidinduced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

The current global pandemic of coronavirus disease 2019 (COVID-19) has affected over 21 million people and caused over half a million deaths within a few months. COVID-19 has become one of the most severe public health crises in recent years. Compared to other pathogenic coronaviruses, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly infectious. Due to the lack of specific and effective treatment or vaccines, disease prevention and early detection are essential for establishing guidelines to mitigate further spread. The potential role of the ocular system in COVID-19 is still not clear but it has gained increasing attention. Here, we reviewed both clinical and research evidence on the ocular manifestations associated with COVID-19, the presence of SARS-CoV-2 in ocular surface tissues and tears, and the potential role of the eye in contracting SARS-CoV-2.