Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression (original) (raw)
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Drug Discovery Today, 2007
Non-alcoholic fatty liver disease (NAFLD) is associated with diabetes, obesity and insulin resistance. The pathogenesis of NAFLD is complex, but modulation of the activities of transcription factors that regulate hepatic lipid and glucose homeostasis may be a key to treating NAFLD. An example of a key transcription factor regulating hepatic lipid metabolism is sterol regulatory element binding proteins (SREBPs), and in this review we present evidence supporting a key role for SREBPs in NAFLD. Currently, the only effective treatment for NAFLD is caloric restriction and peroxisome proliferator activated receptor (PPAR-g) agonists. We suggest that further studies are urgently needed to evaluate modulation of SREBP activity as a potential new treatment for NAFLD.
Journal of Biological Chemistry, 1999
To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of lipogenic enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were consistently low in both wildtype and SREBP-1 ؊/؊ mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1 ؊/؊ mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refed SREBP-1 ؊/؊ livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these lipogenic enzymes were also strikingly lower in SREBP-1 ؊/؊ mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed. The abbreviations used are: SREBP, sterol regulatory elementbinding protein; SRE, sterol regulatory element; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD, stearoyl-CoA desaturase; CYP4A2, cytochrome P-450 4A2; SCAP, SREBP cleavage activating protein; PPAR␣, peroxisome proliferator-activated receptor ␣.
Atherosclerosis, 2005
Hepatic lipase (HL) not only plays an important role in plasma lipoprotein transport, but may also affect intracellular lipid metabolism. We hypothesize that HL expression is regulated as an integral part of intracellular lipid homeostasis. Addition of oleate (1 mM) to HepG2 cells increased HL secretion to 134 ± 14% of control (p < 0.02), and increased the transcriptional activity of a 698-bp HL promoter-reporter construct two-fold. Atorvastatin (10 M) abolished the oleate stimulation. The transcriptional activity of a sterol-regulatory-element binding protein (SREBP)-sensitive HMG-CoA synthase promoter construct was reduced 50% by oleate, and increased 2-3-fold by atorvastatin. Cotransfection with an SREBP-2 expression vector reduced HL promoter activity and increased HMG-CoA synthase promoter activity. Upstream stimulatory factors (USF) are also implicated in maintenance of lipid homeostasis. Co-transfection with a USF-1 expression vector stimulated HL promoter activity 4-6-fold. The USF-stimulated HL promoter activity was not further enhanced by oleate, but almost completely prevented by atorvastatin or co-transfection with the SREBP-2 vector. Opposite regulation by USF-1 and SREBP-2 was also observed with a 318-bp HL promoter construct that lacks potential SRE-like and E-box binding motifs. We conclude that the opposite regulation of HL expression by fatty acids and statins is mediated via SREBP, possibly through interaction with USF.
eLife, 2017
The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for the ma...
Journal of Clinical Investigation, 1997
We have produced transgenic mice whose livers express a dominant positive NH 2 -terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c). Unlike fulllength SREBP-1c, the NH 2 -terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols. We compared SREBP-1c transgenic mice with a line of transgenic mice that produces an equal amount of the NH 2 -terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain. The 1a protein contains a long activation domain with 12 negatively charged amino acids, whereas the 1c protein contains a short activation domain with only 6 such amino acids. As previously reported, livers of the SREBP-1a transgenic mice were massively enlarged, owing to accumulation of triglycerides and cholesterol. SREBP-1c transgenic livers were only slightly enlarged with only a moderate increase in triglycerides, but not cholesterol. The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-1a transgenic mice, but not in 1c transgenic mice. The mRNAs for fatty acid synthase and acetyl CoA carboxylase were elevated 9-and 16-fold in 1a animals, but only 2-and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcription than SREBP-1a when both are expressed at levels approximating those found in nontransfected cells. SREBP-1c became a strong activator only when expressed at supraphysiologic levels. We conclude that SREBP-1a is the most active form of SREBP-1 and that SREBP-1c may be produced when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism. ( J. Clin. Invest. 1997. 99: 846-854.) Key words: SREBP-1 • alternative splicing • cholesterol • fatty acids • transgenic mice
Biochemical and Biophysical Research Communications, 2007
Sterol regulatory element-binding protein (SREBP)-1c is the master regulator of lipogenic gene expression in liver. The mRNA abundance of SREBP-1c is markedly induced when animals are refed after starvation, although the regulatory mechanism is so far unknown. To investigate the mechanism of refeeding response of SREBP-1c gene expression in vivo, we generated a transgenic mouse model that carries 2.2 kb promoter region fused to the luciferase reporter gene. These transgenic mice exhibited refeeding responses of the reporter in liver and adipose tissues with extents essentially identical to those of endogenous SREBP-1c mRNA. The same results were obtained from experiments using adenovirus-mediated SREBP-1c-promoter-luciferase fusion gene transduction to liver. These data demonstrate that the regulation of SREBP-1c gene expression is at the transcription level, and that the 2.2 kb 5 0 -flanking region is sufficient for this regulation. Moreover, when these transgenic or adenovirus-infected mice were placed on insulin-depleted state by streptozotocin treatment, the reporter expression was upregulated as strongly as in control mice, demonstrating that this regulation is not dominated by serum insulin level. These mice are the first models to provide the mechanistic insight into the transcriptional regulation of SREBP-1c gene in vivo.
Journal of Hepatology, 2006
Background/Aims: Alcohol-induced fatty liver is associated with induction of sterol response element binding proteins (SREBPs), transcription factors which regulate expression of genes of lipid synthesis. The contribution of SREBP-1c to alcohol-induced fatty liver and injury was studied. Methods: Wild type and SREBP1c null mice were fed alcohol or control diet by intragastric infusion for 4 weeks. H&E and TUNEL staining, real-time PCR, RT-PCR, and immunoblotting were applied to analyze alcohol-induced liver injury. Results: ALT, plasma homocysteine, liver cholesterol, and TUNEL positive hepatocytes were increased in alcohol-fed mice as compared to control in both genotypes. Liver triglycerides were increased 4-fold in alcohol-fed wild type mice (87.2 ± 7.5 vs. control 22.3 ± 3.1 mg/g liver) but 1.8-fold in alcohol-fed null mice (27.9 ± 4 vs. control 14.5 ± 3.8 mg/g liver). SREBP-2 and HMG CoA reductase were higher in the null than in wild type. Betaine feeding prevented partially the alcohol-induced changes of hepatic lipids and injury in both genotypes. mRNA of Insig-1 was reduced in both genotypes fed alcohol. No change was detected for the SREBP cleavage-activating protein (Scap) or S1P in either genotype fed alcohol. Conclusions: The predominant mechanism of hepatic triglyceride accumulation in the intragastric alcohol fed mouse requires the participation of SREBP-1c. SREBP-2 regulated cholesterol accumulation still occurs.
Journal of Biological Chemistry, 1999
Dietary polyunsaturated fatty acids (PUFA) are negative regulators of hepatic lipogenesis that exert their effects primarily at the level of transcription. Sterol regulatory element-binding proteins (SREBPs) are transcription factors responsible for the regulation of cholesterol, fatty acid, and triglyceride synthesis. In particular, SREBP-1 is known to play a crucial role in the regulation of lipogenic gene expression in the liver. To explore the possible involvement of SREBP-1 in the suppression of hepatic lipogenesis by PUFA, we challenged wild-type mice and transgenic mice overexpressing a mature form of SREBP-1 in the liver with dietary PUFA. In the liver of wild-type mice, dietary PUFA drastically decreased the mature, cleaved form of SREBP-1 protein in the nucleus, whereas the precursor, uncleaved form in the membranes was not suppressed. The decreases in mature SREBP-1 paralleled those in mRNAs for lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase. In the transgenic mice, dietary PUFA did not reduce the amount of transgenic SREBP-1 protein, excluding the possibility that PUFA accelerated the degradation of mature SREBP-1. The resulting sustained expression of mature SREBP-1 almost completely canceled the suppression of lipogenic gene expression by PUFA in the SREBP-1 transgenic mice. These results demonstrate that the suppressive effect of PUFA on lipogenic enzyme genes in the liver is caused by a decrease in the mature form of SREBP-1 protein, which is presumably due to the reduced cleavage of SREBP-1 precursor protein.