SREBP-1c Activation Research Articles

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L - lard; HF-O - olive oil; HF-C - coconut fat; HF-F - fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma omega-3 polyunsaturated fatty acid (omega-3-PUFA) and saturated fatty acid (C(12)-C(14), SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPARalpha-dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA- or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

Liver X Receptor α Interferes with SREBP1c-mediated Abcd2 Expression: NOVEL CROSS-TALK IN GENE REGULATION

The peroxisomal ATP binding cassette (ABC) transporter adrenoleukodystrophy-related protein, encoded by ABCD2, displays functional redundancy with the X-linked adrenoleukodystrophy-associated protein, making ABCD2 up-regulation of therapeutic value. Cholesterol lowering activates human ABCD2 in cultured cells. To investigate in vivo regulation by sterols, we first characterized a sterol regulatory element (SRE) in the murine Abcd2 promoter that is directly bound by SRE-binding proteins (SREBPs). Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation. Using fasting-refeeding and cholesterol loading, SREBP accessibility to the SRE/direct repeat 4 was tested. Results suggest that adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-regulated by concurrent activation of LXRalpha and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXRalpha. Finally, hepatic Abcd2 expression in LXRalpha,beta-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXRalpha as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXRalpha binding sites.

Obstructive sleep apnea: wreaking havoc with homeostasis

the phenotypic characterization of obstructive sleep apnea (OSA) continues to unfold. Recent studies provide evidence that this syndrome has the potential to disturb cardiovascular, neurological, and endocrine homeostatic processes ([1][1], [6][2], [8][3], [9][4]). Li et al. ([5][5]) present

Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly through Synergy with BETA2/E47

Insulin gene expression is regulated by pancreatic beta cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non-beta cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c.BETA2.E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in beta cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with beta cell lipotoxicity.

ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity

The reduction in insulin secretory capacity and beta-cell mass observed in type 2 diabetes is thought to be caused by glucolipotoxicity secondary to hyperglycemia and hyperlipidemia. Our aim in this study was to elucidate the underlying molecular mechanisms. We found a strong correlation between chronic high-glucose treatment and SREBP-1c activation in INS-1 cells and rat islets. Both high-glucose treatment and SREBP-1c activation in INS-1 cells resulted in lipid accumulation, impaired glucose-stimulated insulin secretion, apoptosis, and strikingly similar gene expression patterns, including upregulation of lipogenic and pro-apoptotic genes and downregulation of IRS2, Bclxl and Pdx1. These lipotoxic effects of high glucose were largely prevented by induction of a dominant-negative mutant of SREBP-1c, suggesting SREBP-1c is a major factor responsible for beta cell glucolipotoxicity. Moreover, overexpression of another lipogenic transcription factor, ChREBP, in INS-1 cells did not cause lipotoxicity. Intriguingly, chronic high glucose treatment in INS-1 cells led to pronounced induction of the ER stress marker genes, BIP and Chop10. Treatment of rat islets with both chronic high glucose and two ER stress inducers, thapsigargin and tunicamycin, enhanced SREBP-1 binding to the human IRS2 promoter. These results suggest that SREBP-1 activation caused by ER stress is implicated in beta-cell glucolipotoxicity.

Food for thought: endocannabinoid modulation of lipogenesis

An emerging body of evidence implicates peripheral and central endocannabinoid pathways in the regulation of feeding behavior and body weight. A report in this issue of the JCI demonstrates the presence of a common endocannabinoid-regulated molecular pathway for peripheral lipogenic and central appetitive regulation. This pathway involves the activation of the transcription factor SREBP-1c and its associated enzymes, acetyl-CoA carboxylase-1 and fatty acid synthase, in the liver and hypothalamus. Activation of cannabinoid receptor 1 (CB(1)) in liver plays a key role in increased serum lipid production, fatty liver, and possibly diet-induced obesity. Conversely, stimulation of these receptors in the hypothalamus may lead to an increase in food consumption. Thus, targeting both of these pathways with CB(1) antagonists could promote sustained weight loss and favorable serum lipid profiles in obese patients.

The role of fat tissue in the cholesterol lowering and the pleiotropic effects of statins – statins activate the generation of metabolically more capable adipocytes

Statins have very important influences on adipocyte physiology, particularly via their effects on sterol regulatory element binding proteins (SREBPs), which are extremely important transcription factors for the regulation of adipocyte physiology. SREBP-1c activation in fat cell by the cytosolic cholesterol deprivation through HMG-reductase inhibition is responsible for most of the beneficial effects of statins. Glucose and lipid excess, and oxidative overload coming with energy dense nutrition, which might be deleterious, can be removed from the circulation by adipo-lipogenetic enhancement through the activated SREBP-1c. SREBP-1c causes formation of new small and competent adipocytes, which are insulin and leptin sensitive. Thus, adipocytes gain the ability of fat storing, and much more importantly, fat-burning machines. Statins already have a large and growing number of indications in the treatment of atherovascular diseases. General mechanism for the action of statins is their inhibitory effects on 3-hydroxy 3-methyl glutaryl CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis, particularly in the liver. Recently, the beneficial effects of statins beyond their cholesterol lowering, which are called pleiotropic effects, have been the focus of great attention. Certain characteristics of the statin molecule itself have been proposed to explain these effects. Adipocytes are in the very heart of metabolic regulations. Therefore, the important elements of the pleiotropic effects of statins occur through executive improvements on impaired adipocyte functions by the activation of SREBP-1c.

Hepatic insig-1 or -2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats.

To determine whether the antilipogenic actions of insulin-induced gene 1 (insig-1) demonstrated in cultured preadipocytes also occur in vivo, we infected Zucker diabetic fatty (ZDF) (fa/fa) rats, with recombinant adenovirus containing insig-1 or -2 cDNA. An increase of both proteins appeared in their livers. In control ZDF (fa/fa) rats infected with adenovirus containing the beta-galactosidase (beta-gal) cDNA, triacylglycerols in the liver and plasma rose steeply whereas the insig-infected rats exhibited substantial attenuation of the increase in hepatic steatosis and hyperlipidemia. Insig overexpression was associated with a striking reduction in the elevated level of nuclear sterol regulatory element-binding protein (SREBP)-1c, the activated form of the transcription factor. The mRNA of SREBP-1c lipogenic target enzymes also fell. The mRNA of endogenous insig-1, but not -2a and -2b, was higher in the fatty livers of untreated obese ZDF (fa/fa) rats compared with controls, but the elevation was not sufficient to block the approximately 3-fold increase in SREBP-1c expression and activity. In normal animals, adenovirus-induced overexpression of the insigs reduced the increase in SREBP-1c mRNA and its target enzymes caused by refeeding. The findings demonstrated that both insigs have antilipogenic action when transgenically overexpressed in livers with increased SREBP-1c-mediated lipogenesis. However, the increase in endogenous insig-1 expression associated with augmented lipogenesis may limit it, but is insufficient to prevent it.

Do polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREPB-1 suppression or by correcting essential fatty acid deficiency

Alwayn et al. insightfully argue that the high value of mead acid (20:3 n-9) / arachidonic acid (20:4 n-6) ratio (M/A) in livers from our animals indicates severe deficiency in essential fatty acids, and that the model we employed is therefore close to hepatic steatosis due to essential fatty acid deficiency (EFAD). It depends on how one defines EFAD considering that M/A > 0.4 could be another criterion.1 Overall, EFAD animal models are generally made by feeding them for several weeks diets without essential fatty acids, while the duration is only one week in our protocol for ob/ob mice. In fact, according to our preliminary data, feeding with the basal fat-free diet one week was not long enough to see an appreciable increase in liver triglyceride contents in C57BL/6J mice. Besides, it has been well established that fatty livers observed in ob/ob homozygous mice are caused by increased lipogenesis mediated through sustained activation of SREBP-1c,2 which presumably originates from hyperphagia. Thus, it is unlikely that EFAD played a major role in the development of steatosis in our ob/ob model. However, this does not exclude the possibility that SREBP-1 could be involved in the pathogenesis of steatosis associated with EFAD. Fat-free diet is a key factor for maximum dietary induction of SREBP-1c and essential fatty acids specifically suppress the expression of mature SREBP-1 protein as others and we previously showed.3 It is plausible that EFAD induces hepatic SREBP-1c, which contributes to the development of steatosis.

3P-0766 Bile acids control lipogenesis through a reduction of SREBP-1c activity

3P-0766 Bile acids control lipogenesis through a reduction of SREBP-1c activity