SUMMARY Hepatic lipogenesis is nutritionally regulated, i.e., downregulated during fasting and upregulated during the postprandial state, as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally-regulated lipogenesis, upstream mechanisms governing Srebf1 gene expression remain unclear. Here we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism with therapeutic implications for the treatment of hyperlipidemia.

Background & Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR −/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results CREB3L3 ablation in LDLR −/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. Conclusions CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.

Aims/IntroductionPeroxisome proliferator‐activated receptor‐α (PPARα) is a therapeutic target for hyperlipidemia. K‐877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K‐877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.Materials and MethodsTo compare the effects of K‐877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell‐based PPARα transactivation luciferase assay was carried out. WT and Ppara −/− mice were fed with a moderate‐fat (MF) diet for 6 days, and methionine–choline‐deficient (MCD) diet for 4 weeks containing Feno or K‐877.ResultsIn luciferase assays, K‐877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K‐877 or 0.2% Feno for 6 days, mice in the K‐877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno‐treated animals. These K‐877 effects were blunted in Ppara −/− mice, confirming that K‐877 activates PPARα. In further experiments, K‐877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet‐induced non‐alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.ConclusionsThe present data show that K‐877 is an attractive PPARα‐modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.

Glucocorticoids have various medical uses but are accompanied by side effects. The glucocorticoid receptor (GR) has been reported to regulate the clock genes, but the underlying mechanisms are incompletely understood. In this study, we focused on the suppressive effect of the GR on the expression of Rev‐erbα (Nr1d1), an important component of the clock regulatory circuits. Here we show that the GR suppresses Rev‐erbα expression via the formation of a complex with CLOCK and BMAL1, which binds to the E‐boxes in the Nr1d1 promoter. In this GR‐CLOCK‐BMAL1 complex, the GR does not directly bind to DNA, which is referred to as tethering. These findings provide new insights into the role of the GR in the control of circadian rhythm.

Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21 À/À mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21 À/À mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms.