👤 Kristine Griffett

Cyclopropane FAs (CpFAs) are members of the mammalian lipidome, originating from the diet and gut microbial metabolism. Despite being fully saturated, conformational modeling of CpFAs from C12 to C24 in length revealed that they are bent lipids sharing structural similarities with MUFAs. We therefore hypothesized that CpFAs might share some bioactivities with MUFAs. We modeled and docked a total of 429 known and theoretical CpFAs, MUFAs, and saturated lipids into PPAR α, δ, and γ nuclear receptor structures. CpFAs showed unique spatial binding patterns, especially with PPARδ. In vitro, several CpFAs bound PPARα and δ with potencies comparable to dietary MUFAs, whereas in 3T3-L1 preadipocytes, they upregulated the pan-PPAR target gene Angptl4, indicating downstream functional engagement. These findings suggest that CpFAs share some structural and functional aspects with MUFAs and represent an under-recognized class of metabolically relevant food- and gut-derived lipids. Show less

The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inverse agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression. Show less

Fatty liver, which often accompanies obesity and type 2 diabetes, frequently leads to a much more debilitating hepatic disease including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Current pharmacological therapies lack conclusive efficacy and thus treatment options are limited. Novel therapeutics that suppress either hepatic lipogenesis and/or hepatic inflammation may be useful. Here, we describe the development of the first selective synthetic LXR inverse agonist (SR9238) and demonstrate that this compound effectively suppresses hepatic lipogenesis, inflammation, and hepatic lipid accumulation in a mouse model of non-alcoholic hepatosteatosis. SR9238 displays high potency for both LXRα and LXRβ (40-200 nM IC50) and was designed to display liver specificity so as to avoid potential side effects due to suppression of LXR in the periphery. Unexpectedly, treatment of diet-induced obese mice with SR9238 suppressed plasma cholesterol levels. These data indicate that liver-selective LXR inverse agonists may hold utility in the treatment of liver disease. Show less