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Hepatic steatosis is caused by metabolic imbalances that could be explained in part by an increase in de novo lipogenesis that results from increased sterol element binding protein 1 (SREBP-1) activity. The nuclear receptor liver receptor homolog 1 (LRH-1) is an important regulator of intermediary metabolism in the liver, but its role in regulating lipogenesis is not well understood. Here, we have assessed the contribution of LRH-1 SUMOylation to the development of nonalcoholic fatty liver disease (NAFLD). Mice expressing a SUMOylation-defective mutant of LRH-1 (LRH-1 K289R mice) developed NAFLD and early signs of nonalcoholic steatohepatitis (NASH) when challenged with a lipogenic, high-fat, high-sucrose diet. Moreover, we observed that the LRH-1 K289R mutation induced the expression of oxysterol binding protein-like 3 (OSBPL3), enhanced SREBP-1 processing, and promoted de novo lipogenesis. Mechanistically, we demonstrated that ectopic expression of OSBPL3 facilitates SREBP-1 processing in WT mice, while silencing hepatic Osbpl3 reverses the lipogenic phenotype of LRH-1 K289R mice. These findings suggest that compromised SUMOylation of LRH-1 promotes the development of NAFLD under lipogenic conditions through regulation of OSBPL3., Introduction Hepatic steatosis is characterized by the excessive accumulation of triglycerides as a consequence of an imbalance between the acquisition and disposal of fatty acids. Increased hepatic uptake of adipose [...]

Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect [...]

Abstract Background Overactivity and/or dysregulation of the endocannabinoid system (ECS) contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1) in adipocyte function and CB1-receptor deficient (CB1-/-) mice are resistant to high fat diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. Methods We evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF) or a high-fat/fish oil (HF/FO) diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning. Results The adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL) activities were also not altered in CB1-/- mice. Conclusions These findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non-oxidative pathways.

Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1 -deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. Conclusions Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1–PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamine-induced metabolism and signaling to promote hepatocellular carcinogenesis. [ABSTRACT FROM AUTHOR]

Summary: As NAD+ is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38—both NAD+ consumers—increases NAD+ bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD+ precursor with the ability to increase NAD+ levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD+ levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function. [ABSTRACT FROM AUTHOR]

We previously reported that in high fat (HF, 24% w/w)-fed C57B16 mice, partial substitution of saturated fat diet for fish oil (FO) aggravated the impaired glucose disposal under hyperinsulinemic conditions. Surprisingly, hepatic insulin sensitivity was maintained under these conditions. However, the HF content of the diet and the degree of FO substitution might have been too low to affect hepatic insulin sensitivity. We therefore compared metabolic effects of chow (CTRL), HF (36% w/w) and HF/FO (21/15% w/w) diets fed to C57B16 mice for 6 weeks. Body weight and adipocyte size increased upon HF feeding compared to the CTRL group. These effects were even more pronounced in mice fed the HF/FO diet. Fasting blood glucose and plasma insulin levels were significantly elevated in the HF and HF/FO groups in comparison to controls. Gene expression levels of enzymes involved in hepatic de novo lipogenesis, in particular Scdl, were increased by HF feeding; this effect was reversed by feeding the HF/FO diet. Concomitantly, hepatic monounsaturated fatty acid (MUFA) content was significantly increased in the HF group and normalized in the HF/FO group (CTRL 24±5, HF 40± 12, HF/FO 22±3 mol%). Basal hepatic glucose production (HGP) was significantly reduced in the HF/FO group only (CTRL 131±18, HF 139±14, HF/FO 105±11 µmol/kg/min). Insulin sensitivity of HGP, however, was only marginally impaired in mice fed HF or HF/FO diets (insulin-mediated suppression of HGP: CTRL' -40, HF-27, HF/FO -28%). Insulin sensitivity of metabolic glucose clearance (MCR) was reduced in the HF group and even more reduced in mice fed the HF/FO diet (insulin-mediated stimulation of MCR: CTRL +304%, HF +286%, HF/FO +186%). Respiratory Exchange Ratio in mice fed the HF/FO diet was consistently lower compared to HF-fed animals, while oxygen consumption was similar. Moreover, expression levels of fatty acid oxidation genes in skeletal muscle were significantly higher in the HF/FO group compared to the HF group. Taken together, our data show that FO aggravates HF-induced peripheral insulin resistance in mice. Furthermore, it reduces basal hepatic glucose production in HF-fed animals, while lipogenic gene expression and MUFA content are decreased. Hepatic insulin sensitivity, on the other hand, is not affected by FO substitution of a HF diet. [ABSTRACT FROM AUTHOR]

LXR is a nuclear hormone receptor that coordinates lipid and cholesterol metabolism upon activation by oxysterols. Recently, it was proposed that LXR acts as a glucose sensor in the liver and that glucose and its metabolite glucose-6-phosphate are able to activate LXR in vitro at physiological concentrations. The aim of this study was to assess the functional relevance of the major hepatic LXR isoform in the control of hepatic and peripheral glucose metabolism in mice. Glucose metabolism was studied in fasted male LXR-alpha knockout (KO) mice and their wildtype (WT) littermates by infusing [U13C]glucose, [2-13C]glycerol, [1-2H]galactose and paracetamol for 6 hours, followed by mass isotopomer distribution analysis. Furthermore, hyperinsulinemic euglycemic clamps were performed using [U-13C]glucose. Blood glucose levels during steady state conditions were significantly reduced in LXRalpha KO mice (KO 7.3±0.5 WT 9.5±1.9 mmol/l, p<0.05). Whole body glucose turnover was significantly lower in LXRalpha null mice compared to wildtype littermates (KO 129.6±12.8 WT 159.1±26.2 µmol/kg/min, p<0.05). LXRalpha deficiency did not affect gluconeogenic flux (KO 97.9±9.5 WT 109.±17.1 µmol/kg/min, NS). However, all fluxes affecting the glucose-6-phosphate pool, i.e. through glycogen synthase (Gs), glycogen phosphorylase (Gp), glucose-6-phosphatase (G6pase) and glucokinase (Gk) were significantly lower in LXRalpha null mice compared to wildtype littermates. Expression levels of genes encoding Pyruvate Kinase (Pk), Gk and Gp were significantly reduced by LXRalpha deficiency. Glucose balance, i.e., the difference between G6pase and Gk fluxes was lower in LXRalpha null mice (KO 119.5±11.9 WT 142.8±27.1 µmol/kg/min, p<0.05). Glycogen balance, i.e., the difference between Gs and Gp fluxes was not altered in LXRalpha null mice (KO-14.4±8.1 WT -20.6±18.5 µmol/kg/min, NS). Metabolic clearance of glucose was not affected by LXRalpha deficiency (KO 18.2±2.7 WT 16.9±1.8 µmol/kg/min, NS). Under hyperinsulinemic conditions, LXRalpha null mice and wildtype littermates exhibited similar hepatic glucose production and metabolic glucose clearance rates, indicative for unaltered hepatic and peripheral insulin sensitivity. In summary, LXRalpha deficiency results in disturbed hepatic glucose-6-phosphate metabolism in mice. As a result, hepatic glucose output is impaired, leading to decreased blood glucose levels. [ABSTRACT FROM AUTHOR]