scispace - formally typeset
Search or ask a question
Journal ArticleDOI

SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

01 May 2002-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 109, Iss: 9, pp 1125-1131
TL;DR: The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice and form the subject of this review.
Abstract: Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1–4). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: In the endoplasmic reticulum (ER), secretory and transmembrane proteins fold into their native conformation and undergo posttranslational modifications important for their activity and structure as mentioned in this paper.
Abstract: In the endoplasmic reticulum (ER), secretory and transmembrane proteins fold into their native conformation and undergo posttranslational modifications important for their activity and structure. When protein folding in the ER is inhibited, signal transduction pathways, which increase the biosynthetic capacity and decrease the biosynthetic burden of the ER to maintain the homeostasis of this organelle, are activated. These pathways are called the unfolded protein response (UPR). In this review, we briefly summarize principles of protein folding and molecular chaperone function important for a mechanistic understanding of UPR-signaling events. We then discuss mechanisms of signal transduction employed by the UPR in mammals and our current understanding of the remodeling of cellular processes by the UPR. Finally, we summarize data that demonstrate that UPR signaling feeds into decision making in other processes previously thought to be unrelated to ER function, e.g., eukaryotic starvation responses and differentiation programs.

2,892 citations

Journal ArticleDOI
TL;DR: In this article, the authors quantified the biological sources of hepatic and plasma lipoprotein TAG in NAFLD patients, using stable isotopes for four days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipid TAG.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD Patients (5 male and 4 female; 44 ± 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia Of the TAG accounted for in liver, 590% ± 99% of TAG arose from NEFAs; 261% ± 67%, from DNL; and 149% ± 70%, from the diet The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids DNL was elevated in the fasting state and demonstrated no diurnal variation These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD

2,870 citations


Cites result from "SREBPs: activators of the complete ..."

  • ...Given previous observations of higher fed-state DNL (23) and the known stimulatory effect of insulin on fatty acid synthesis (24), we were surprised that fed-state lipogenesis assessed at 1500 in tTRL TAG did not differ from values obtained in the fasting Figure 1 Model of lipid flux through the liver....

    [...]

Journal ArticleDOI
TL;DR: Recent advances in the understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis are highlighted.
Abstract: Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.

1,904 citations


Cites background from "SREBPs: activators of the complete ..."

  • ...In the nucleus, SREBP-1c transcriptionally activates all genes required for lipogenesis (15, 23)....

    [...]

  • ...which also can be desaturated to form oleic acid (C18:1) (15)....

    [...]

Journal ArticleDOI
TL;DR: A conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis will progressively support the development of new strategies to treat human cancer.
Abstract: Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

1,850 citations

Journal ArticleDOI
24 Jun 2011-Science
TL;DR: Recent mechanistic insights into nonalcoholic fatty liver disease are discussed, focusing primarily on those that have emerged from human genetic and metabolic studies.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.

1,831 citations

References
More filters
Journal ArticleDOI
TL;DR: It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.
Abstract: Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

5,146 citations


"SREBPs: activators of the complete ..." refers background in this paper

  • ...Metformin stimulates AMP-activated protein kinase (AMPK), an enzyme that inhibits lipid synthesis through phosphorylation and inactivation of key lipogenic enzymes (41)....

    [...]

  • ...In rat hepatocytes, metformin-induced activation of AMPK also leads to decreased mRNA expression of SREBP-1c and its lipogenic target genes (41), but the basis of this effect is not understood....

    [...]

Journal ArticleDOI
Paul Angulo1
TL;DR: Nonalcoholic fatty liver disease is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as due to cirrhosis and hepatocellular carcinoma, which occurs in a minority of patients.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is present in up to one third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn, exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as due to cirrhosis and hepatocellular carcinoma, which occurs in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.

4,705 citations

Journal Article

3,896 citations


"SREBPs: activators of the complete ..." refers background in this paper

  • ...SREBPs in disease Many individuals with obesity and insulin resistance also have fatty livers, one of the most commonly encountered liver abnormalities in the US (37)....

    [...]

Journal ArticleDOI
02 May 1997-Cell
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.

3,626 citations


"SREBPs: activators of the complete ..." refers background in this paper

  • ...This form of regulation is manifest not only in cultured cells (1), but also in the livers of rodents fed cholesterol-enriched diets (19)....

    [...]

  • ...SREBPs stimulate LDL receptor expression, but they also enhance lipid synthesis (1), so their net effect on plasma lipoprotein levels depends on a balance between opposing effects....

    [...]

  • ...2 through the use of alternative transcription start sites that produce alternate forms of exon 1, designated 1a and 1c (1)....

    [...]

  • ...bound to the endoplasmic reticulum (ER) (1, 5)....

    [...]

  • ...The net result is that SREBPs lose their access to S1P and S2P in the Golgi apparatus, so their bHLH-Zip domains cannot be released from the ER membrane, and the transcription of target genes ceases (1, 5)....

    [...]

Journal ArticleDOI
01 Aug 2001-Diabetes
TL;DR: It is concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity.
Abstract: Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU m(-2) min(-1)) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m(2) Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs -84% in control subjects; P = 0003) Postabsorptive hepatic glucose production (HGP), measured by [6,6-(2)H(2)]glucose, was normal In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs 84% in control subjects (P = 0002) Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulin-mediated suppression of HGP There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance

2,367 citations