Disorders of lipid and lipoprotein metabolism and transport are responsible for the development of a large spectrum of pathologies, ranging from cardiovascular diseases, to metabolic syndrome, even to tumour development. Recently, a deeper knowledge of the molecular mechanisms that control our biological clock and circadian rhythms has been achieved. From these studies it has clearly emerged how the molecular clock tightly regulates every aspect of our lives, including our metabolism. This review analyses the organisation and functioning of the circadian clock and its relevance in the regulation of physiological processes. We also describe metabolism and transport of lipids and lipoproteins as an essential aspect for our health, and we will focus on how the circadian clock and lipid metabolism are greatly interconnected. Finally, we discuss how a deeper knowledge of this relationship might be useful to improve the recent spread of metabolic diseases.

The liver X receptors (LXRs) have been shown to affect lipoprotein plasma profile, lipid metabolism, and reverse cholesterol transport (RCT). In the present study, we investigated whether a short-term administration of the synthetic LXR agonist T0901317 (T0) to mice may affect RCT by modulating the capacity of plasma to promote cellular lipid efflux. Consistent with previous data, the pharmacological treatment of mice caused a significant increase of macrophage-derived [ 3 H]cholesterol content in plasma, liver, and feces and resulted in improved capacity of plasma to promote cellular cholesterol release through passive diffusion and scavenger receptor class B type I (SR-BI)-mediated mechanisms. Differently, plasma from treated mice possessed similar or reduced capacity to drive lipid efflux via ABCA1. Consistent with these data, the analysis of plasma HDL fractions revealed that T0 caused the formation of larger, lipid-enriched particles. These results suggest that T0 promotes in vivo RCT from macrophages at least in part by inducing an enrichment of those HDL subclasses that increase plasma capacity to promote cholesterol efflux by passive diffusion and SR-BI-mediated mechanisms.-Zanotti, I., F. Potì, M. Pedrelli, E. Favari, E. Moleri, G. Franceschini, L. Calabresi, and F. Bernini. The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential. J. Lipid Res. 2008. 49: 954-960.

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Objective-To assess the role of apolipoprotein (apo) E in macrophage reverse cholesterol transport (RCT) in vivo. Methods and Results-ApoE exerts an antiatherosclerotic activity by regulating lipoprotein metabolism and promoting cell cholesterol efflux. We discriminated between macrophage and systemic apoE contribution using an assay of macrophage RCT in mice. The complete absence of apoE lead to an overall impairment of the process and, similarly, the absence of apoE exclusively in macrophages resulted in the reduction of cholesterol mobilization from macrophages to plasma, liver, and feces. Conversely, expression of apoE in macrophages is sufficient to promote normal RCT even in apoE-deficient mice. The mechanisms accounting for these results were investigated by evaluating the first step of RCT (ie, cholesterol efflux from cells). Macrophages isolated from apoE-deficient mice showed a reduced ability to release cholesterol into the culture medium, whereas the apoB-depleted plasma from apoE-deficient and healthy mice possessed a similar capacity to promote cellular lipid release from cultured macrophages. Conclusion-Our data demonstrate, for the first time to our knowledge, that apoE significantly contributes to macrophage RCT in vivo and that this role is fully attributable to apoE expressed in macrophages. A polipoprotein E (apoE) is a structural component of several lipoproteins, including very-low-density lipoproteins (LDLs) and their remnants, chylomicron remnants, and high-density lipoproteins (HDL). 1 ApoE is predominantly synthesized by the liver and accomplishes its physiological role by driving the hepatic clearance of the lipoproteins on which it resides through binding with very LDL and chylomicron-remnant receptors 2 and inhibiting triglyceride lipolysis. 3 Altogether, these activities contribute to the regulation of circulating lipoprotein levels. Several population studies 3-5 associated apoE defects with lipoprotein disorders and increased cardiovascular risk, thus revealing the key role played in atheroprotection. This beneficial activity was further demonstrated by the generation of mice lacking the apoE gene, characterized by hypercholesterolemia and abnormal lipid deposition in the proximal aorta and liver, even when receiving a normal chow diet. 6,7 Beyond the influence on lipoprotein metabolism, apoE atheroprotective activity is also related to the promotion of cholesterol efflux from macrophages. 8,9 Cholesterol efflux is the first ratelimiting step of reverse cholesterol transport (RCT), the process by which excess cholesterol is delivered from peripheral tissues to the liver for final excretion into the feces. 10 Macrophage is the primary cell type overloaded with cholesterol within atherosclerotic lesions, and this cholesterol pool is the most important for atherosclerosis development and progression. 11 Thus, the RCT that involves macrophage-derived cholesterol became fundamental concerning atheroprotection. Macrophage RCT can be estimated with a radioisotope-based assay, whose appli...

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.

The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXR␣␤ Ϫ/Ϫ mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXR␣␤ Ϫ/Ϫ mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXR␣␤ Ϫ/Ϫ mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXR␣␤ Ϫ/Ϫ mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from V O2 and V CO2 was significantly higher in LXR␣␤ Ϫ/Ϫ than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXR␣␤ Ϫ/Ϫ mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXR␣␤ Ϫ/Ϫ mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXR␣␤ Ϫ/Ϫ mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXR␣␤ Ϫ/Ϫ mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development. high carbohydrate; energy regulation; metabolism; insulin resistance OBESITY AND ASSOCIATED COMPLICATIONS such as cardiovascular diseases and diabetes represent a major health problem in Western countries. The molecular mechanisms behind metabolic disorders are poorly understood but typically involve deregulation of cholesterol, lipid, and carbohydrate metabolism as well as impaired insulin signaling. The principal function of insulin is to maintain blood glucose and nonesterified fatty acid (NEFA) concentrations nearly constant despite the fluctuations during dietary intake of carbohydrates and lipids. De novo lipogenesis (DNL), i.e., the synthesis of fatty acids from nonlipid substrates, mainly carbohydrates, is nutritionally regulated. Both glucose and insulin signaling pathways are engaged in response to dietary carbohydrates to synergistically induce expression of glycolytic and lipogenic genes in the liver (12).Liver and adipose tissue are the two main sites of DNL in mice (32, 46). In humans, DNL capacity of adipose tissue remains controversial. Diraison et al. (14) found that a highcarbohydrate diet (HCD) in humans does not upregulate DNL or expression of lipogenic genes in adipocytes, whereas hepatic DNL is increased two-to threefold. Letexier et al. (32) concluded that DNL is reduced in human adipose tissue compared with rodents due to a lower abundance of sterol-responsive element-binding protein-1c (SREBP-1c) protein (...

The response to overfeeding is sex dependent, and metabolic syndrome is more likely associated to obesity in men or postmenopausal women than in young fertile women. We hypothesized that obesity-induced metabolic syndrome is sex dependent due to a sex-specific regulation of the fatty acid (FA) synthesis pathways in liver and white adipose depots. We aimed to identify distinctive molecular signatures between sexes using a lipidomics approach to characterize lipid species in liver, perigonadal adipose tissue, and inguinal adipose tissue and correlate them to the physiopathological responses observed. Males had less total fat but lower subcutaneous on visceral fat ratio together with higher liver weight and higher liver and serum triglyceride (TG) levels. Males were insulin resistant compared to females. Fatty acid (FA) and TG profiles differed between sexes in both fat pads, with longer chain FAs and TGs in males compared to that in females. Remarkably, hepatic phospholipid composition was sex dependent with more abundant lipotoxic FAs in males than in females. This may contribute to the sexual dimorphism in response to obesity towards more metaflammation in males. Our work presents an exhaustive novel description of a sex-specific lipid signature in the pathophysiology of metabolic disorders associated with obesity in ob / ob mice. These data could settle the basis for future pharmacological treatment in obesity. Electronic supplementary material The online version of this article (10.1186/s13293-019-0225-y) contains supplementary material, which is available to authorized users.

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