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Curr Opin Lipidol. Author manuscript; available in PMC 2010 June 1.
Published in final edited form as:
PMCID: PMC2874866
NIHMSID: NIHMS180986

Dissecting the Role of Insulin Resistance in the Metabolic Syndrome

Abstract

Purpose of Review

Over twenty years ago, insulin resistance was postulated to play a central role in the pathogenesis of the metabolic syndrome. However, this has been difficult to prove, leading to a great deal of controversy within the field. Recent studies in mice and humans with genetic defects in insulin signaling have allowed us, for the first time, to dissect which features of the metabolic syndrome can be caused by insulin resistance.

Recent Findings

Mice with liver specific knockout of the insulin receptor (LIRKO) show that hepatic insulin resistance can produce (1) hyperglycemia; (2) increased Apob secretion and atherosclerosis; and (3) increased biliary cholesterol secretion and cholesterol gallstones. Many of these changes may be due to dis-inhibition of the transcription factor, FoxO1. Yet, neither LIRKO mice nor humans with insulin receptor mutations develop the hypertriglyceridemia or hepatic steatosis associated with the metabolic syndrome.

Conclusion

These data point to a central role for insulin resistance in the pathogenesis of the metabolic syndrome, as hyperglycemia, atherosclerosis, and cholesterol gallstones can all be caused by insulin resistance. However, hypertriglyceridemia and hepatic steatosis are not due directly to insulin resistance, and should be considered pathogenically distinct features of the metabolic syndrome.

Keywords: Hepatic fatty acid metabolism, sterol regulatory element binding protein-1c, forkhead box O1, cholesterol gallstones, dyslipidemia

Introduction

The prevalence of the metabolic syndrome has reached epidemic proportions in our society, with more than one in four adults in the United States affected [1]. This disorder is characterized by a constellation of symptoms which includes obesity, dyslipidemia with hypertriglyceridemia and low HDL-cholesterol, glucose intolerance, gallstones, hypertension and non-alcoholic fatty liver disease (NAFLD)[2]. Insulin resistance was suggested to play a central role in the development of the metabolic syndrome over twenty years ago [3]. Since then, we have accrued a large body of literature documenting a correlation between insulin resistance, dyslipidemia, atherosclerosis, gallstones and NAFLD. However, proving a causal role for insulin resistance has remained difficult [4].

Insulin Action and Insulin Resistance

Insulin resistance is defined clinically in terms of the failure of insulin to maintain glucose homeostasis. Hence, various measurements of glucose and insulin are used to assess insulin resistance, with the hyperinsulinemic euglycemic clamp being the gold standard. While this definition is very useful clinically, it fails to address the fact that insulin regulates many processes within the cell in addition to glucose metabolism. Furthermore, it implies that all of the processes regulated by insulin become resistant to insulin in parallel with glucose metabolism, and this is likely false.

Here, we will use the phrase insulin resistance to mean a defect in insulin signaling. Since a comprehensive description of insulin signaling is beyond the scope of this review, we will highlight several of the major nodes in the insulin signaling pathway, and two transcription factors, Foxo1 and Sterol Regulatory Element Binding Protein (Srebp)-1c, that are regulated by insulin. This will serve to illustrate how defects in insulin signaling could contribute to the metabolic syndrome, but it should be recognized that many other signaling events and targets are involved.

Insulin binds to and activates the insulin receptor, a tyrosine kinase residing in the plasma membrane, which in turn phosphorylates targets such as the insulin receptor substrate (IRS) proteins, Irs1 and Irs2 (reviewed in [5]). This initiates a complex cascade of events. One major branch of insulin signaling is mitogen activated protein (MAP) kinase, which is primarily associated with the proliferative effects of insulin. The other major branch of insulin signaling is the class Ia forms of phosphatidylinositol 3-kinase (PI 3-kinase), which mediates most of the metabolic effects of insulin. PI 3-kinase, in turn, activates the atypical PKCs, PKC-λ (lambda) and PKC-ζ (zeta), and Akt.

Akt inactivates Foxo1 by phosphorylating it on residues Thr-24, Ser-256, and Ser-319 [6]. Phosphorylated Foxo1 is excluded from the nucleus, and targeted for degradation. Insulin may also regulate Foxo1 by acetylation [7] and modulation of its transcriptional co-activator, peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC)-1α [8;9]. In the absence of insulin, Foxo1 activates transcription both directly, by binding to insulin response elements (IREs) in the promoters of its target genes [10], and indirectly by co-activating other transcription factors [11].

Foxo1 activates expression of a diverse set of targets, including the gluconeogenic enzymes, glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pck1). Therefore, activation of Foxo1 increases fasting glucose and impairs glucose tolerance [12] whereas knockdown of Foxo1 decreases gluconeogenic gene expression and decreases serum glucose levels [13;14]. Microsomal triglyceride transfer protein (Mttp), which promotes the lipidation of apolipoprotein B (Apob), a rate-determining step in VLDL secretion [15], is also a target of Foxo1[16]. Thus, Apob secretion is increased by expression of constitutively active Foxo1, and decreased by knockdown of Foxo1 [16]. Finally, Foxo1 promotes the expression of the cholesterol efflux transporters, Abcg5 and Abcg8 [17]. These transporters form heterodimers which reside on the canalicular membrane of the hepatocyte and regulate the efflux of cholesterol into the bile [18;19].

The signal transduction pathways regulating Srebp-1c are not as clear. It has been suggested that Irs1 is more important than Irs2 [20;21] in the activation of Srebp-1c, but this has not been observed in all studies [22]. Mice lacking PI 3-kinase activity in the liver show decreased expression of Srebp-1c and its target gene, fatty acid synthase, as well as reduced serum and hepatic triglycerides, implicating a role for PI 3-kinase in the regulation of Srebp-1c [23]. Consistent with this, reconstitution of PKC-λ in the livers of these mice increased Srebp-1c but reconstitution of Akt, the other major target of PI 3-kinase, did not [23]. Moreover, knockout of PKC-λ reduces Srebp-1c, its lipogenic targets, and triglyceride accumulation, in the liver [24]. Taken together, these data indicate that insulin activates Srebp-1c through a pathway involving Irs1, PI 3-kinase, and PKC-λ, though other pathways have also been implicated [25;26].

Insulin stimulates Srebp-1c transcription [27] and maturation [28], and could further regulate Srebp-1c by phosphorylation [29;30] and ubiquitination [31]. Srebp-1c promotes expression of all of the genes required for the synthesis of monounsaturated fatty acids [32;33]. Consequently, mice that lack Srebp-1c show a diminished lipogenic response to insulin [34] and mice overexpressing Srebp-1c show increased lipogenic gene expression and increased hepatic triglyceride content [32]. Moreover, in leptin deficient ob/ob mice, which show massive hepatic steatosis, knockout of Srebp-1c dramatically reduces lipogenic gene expression and the accumulation of hepatic triglycerides [35]. This indicates that Srebp-1c is necessary for the development of hepatic steatosis.

Insulin Resistance In Vivo

Liver Insulin Receptor Knockout (LIRKO) mice were created using the cre/LoxP system to specifically ablate the insulin receptor in hepatocytes, resulting in >95% deletion of the insulin receptor in the liver [36;37]. Therefore, these mice manifest complete hepatic insulin resistance, and show increased expression of the gluconeogenic genes, increased hepatic glucose output, marked glucose intolerance and hyperglycemia [36;37].

LIRKO mice show normal levels of serum cholesterol, but the distribution of this cholesterol is pro-atherogenic, with increased VLDL cholesterol and decreased HDL cholesterol, recapitulating some features of the dyslipidemia associated with the metabolic syndrome in humans [38]. The mechanism underlying the decrease in HDL cholesterol remains under investigation, but the increase in VLDL cholesterol is due, in part, to increased secretion of Apob, the principle protein component of the VLDL particle [38]. This is consistent with the facts that insulin inhibits Apob secretion both by promoting its degradation [39;40], and preventing Foxo1 mediated transcription of Mttp [16]. In addition, on an atherogenic diet, LIRKO mice have decreased expression of the LDL receptor, a key determinant of serum cholesterol levels [38]. This results in decreased LDL clearance, and diet-dependent hypercholesterolemia [38]. Consequently, LIRKO mice are exquisitely sensitive to atherosclerosis, with 100% of LIRKO mice, but no controls, developing atherosclerosis after three to four months on an atherogenic diet [38].

LIRKO mice also show marked derangements in the expression of bile acid synthetic enzymes. Bile acids play an important role in the absorption of dietary cholesterol, but also appear to function as hormones in the regulation of energy metabolism [41]. A decrease in Cyp7b1 is one of the most prominent changes in gene expression observed in the LIRKO liver by microarray analysis [17]. Cyp7b1 is the first enzyme of the acidic pathway of bile acid synthesis specific to that pathway. The acidic pathway produces largely chenodeoxycholate (CDCA).

Consequently, LIRKO bile shows a relative decrease in the muricholates, the metabolites of chenodeoxycholate, making it more lithogenic [17]. Whether these changes in the bile salt profile also alter energy expenditure has yet to be determined, but could be relevant to the metabolic syndrome phenotype. Interestingly, Cyp7b1 mRNA levels are also decreased in the livers of mice made insulin deficient by streptozotocin treatment, and mice that are insulin resistant secondary to leptin deficiency or high fat feeding, indicating the importance of insulin in the regulation of this enzyme [17].

In addition to these changes in bile acid metabolism, the cholesterol transporters Abcg5 and Abcg8 are increased three-fold at the mRNA levels in LIRKO livers, consistent with increased Foxo1 activity. This results in a three-fold increase in biliary cholesterol secretion and an increase in the cholesterol saturation index [17]. This finding is important because increased biliary secretion contributes to cholesterol gallstone formation in obese humans [42;43]. Not surprisingly, when fed a lithogenic diet, 36% of LIRKO mice, but none of the controls, develop cholesterol gallstones after one week[17].

Some of these metabolic parameters have been studied in another model of hepatic insulin resistance, in which the major targets of the insulin receptor, Irs1 and Irs2, are both ablated in the liver (LIrs1,2DKO mice). LIrs1,2DKO mice show increased expression of G6pc and Pck1,hyperglycemia and hyperinsulinemia [44]. Genetic ablation of Foxo1 in the livers of LIrs1,2DKO mice decreases gluconeogenic gene expression, fasting glucose, and insulin levels, underscoring the importance of Foxo1 in this phenotype [22;44].

The metabolic syndrome is also associated with increased expression of Srebp-1c, lipogenesis, triglyceride secretion, and hepatic triglycerides [45]. These features of the metabolic syndrome are conspicuously absent in mice and humans with defects in the insulin receptor. The secretion of VLDL triglycerides is decreased by 50% in LIRKO mice, even as secretion of Apob is increased. The uncoupling of triglyceride and Apob secretion results in VLDL particles that are relatively enriched in cholesterol, and potentially more atherogenic. Similarly, LIrs1,2DKO mice also show a 50% decrease in VLDL triglyceride secretion, and both models show a 50% reduction in serum triglycerides [22;38]. Concomitant with these changes, both LIRKO and LIrs1,2DKO mice have more than two-fold reductions in Srebp-1c, decreased expression of the lipogenic enzymes, and normal hepatic triglyceride content [22;38;44]. Similarly, humans with mutations in the insulin receptor show decreased levels of serum triglycerides and VLDL that is relatively enriched in cholesterol; moreover, they do not show increased levels of lipogenesis or hepatic triglycerides[46].

There are at least two possible explanations why hypertriglyceridemia and hepatic steatosis develop in the metabolic syndrome, but not in mice or humans with insulin receptor mutations. First, insulin resistance in the metabolic syndrome may be due to defects in the downstream components of the insulin signaling pathway, rather than the insulin receptor itself [5, 21]. This would produce a fundamentally different type of insulin resistance. Defects in the insulin receptor produce “complete insulin resistance,” in which all pathways fail to respond to insulin, as observed in LIRKO livers. In contrast, lesions in the distal portion of the insulin signaling cascade produce “pathway specific insulin resistance” as they affect only a subset of the processes regulated by insulin. It has been postulated that insulin resistance in the metabolic syndrome is pathway specific: although the Akt/FoxO1 pathway becomes resistant, the PKC-λ / Srebp-1c pathway does not. Hence, insulin loses its ability to suppress FoxO1, gluconeogenic enzymes, Mttp, Abcg5 and Abcg8, but retains its ability to stimulate Srebp-1c and the lipogenic enzymes. According to this model, hyperinsulinemia, which evolves with the metabolic syndrome, maximally stimulates Srebp-1c and lipogenesis, and this is the major driver of hypertriglyceridemia and hepatic steatosis in the metabolic syndrome [2;3;5;47]. Consistent with this, humans with defects in Akt develop hypertriglyceridemia and hepatic steatosis, though humans with defects in the insulin receptor do not [46].

Second, the metabolic syndrome is triggered by environmental and genetic factors, which could exert effects that are independent of insulin resistance. Srebp-1c is regulated not only by insulin, but by different dietary components, such as carbohydrates and polyunsaturated fatty acids [48;49], and hormones, including endocannabinoids and leptin. [50;51]. Thus, changes in the hormonal and metabolic milieu that are unrelated to insulin could induce Srebp-1c, hypertriglyceridemia and hepatic steatosis independently of insulin resistance in the metabolic syndrome.

Summary

The metabolic syndrome in humans is an exceedingly complex disorder, characterized by numerous derangements in the hormonal and metabolic milieu. Insulin resistance, i.e. a defect in insulin signaling, is only one of these derangements. LIRKO mice, LIrs1,2DKO mice and humans with insulin receptor mutations have enabled us to dissect those components of the metabolic syndrome which are due to insulin resistance, from those which are not. LIRKO mice show that hepatic insulin resistance produces hyperglycemia, increased apoB secretion, and increased biliary cholesterol secretion. Many of these changes may be due to dis-inhibition of Foxo1, which appears to regulate all of these processes. In contrast, activation of Srebp-1c, hypertriglyceridemia and hepatic steatosis can not be attributed to hepatic insulin resistance—i.e., an inability of insulin to activate its targets in the liver. They are instead driven by either hyperinsulinemia with continued responsiveness of Srebp-1c to insulin, other factors present in the metabolic syndrome, or both.

Conclusions

The role of insulin resistance in the metabolic syndrome has been a topic of intense debate [4]. Recent data suggest that insulin resistance is sufficient to produce not only glucose intolerance, but also increased biliary cholesterol secretion, atherosclerosis, and cholesterol gallstones. This argues that the metabolic syndrome is not merely a collection of abnormalities that should be considered and treated independently, as some experts have advocated [4]. Rather, the metabolic syndrome is truly a syndrome, in which many, though not all, components arise from a common pathophysiological disturbance, namely insulin resistance. Further work will be necessary to define the precise molecular defects in insulin signaling that underlie the metabolic syndrome in humans.

Figure 1
The insulin signaling cascade. Insulin triggers a complex, branching network of signaling events. Shown here is a summary of the major nodes of this cascade, two important transcription factors, Foxo1 and Srebp-1c, and their targets.

Acknowledgments

This work was funded in part by grant DK063696-05 (SBB).

Reference List

1. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA. 2004;291:2847–2850. [PubMed]
2. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am. 2004;33:283–303. [PubMed]
3. Reaven GM. Banting lecture: Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607. [PubMed]
4. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28:2289–2304. [PubMed]
5. Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol. 2006;68:123–158. [PubMed]
6. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 1999;96:857–868. [PubMed]
7. Accili D, Arden KC. FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation. Cell. 2004;117:421–426. [PubMed]
8. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423:550–555. [PubMed]
9. Li X, Monks B, Ge Q, Birnbaum MJ. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007;447:1012–1016. [PubMed]
10. Foufelle F, Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J. 2002;366:377–391. [PubMed]
11. Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol. 2004;24:7931–7940. [PMC free article] [PubMed]
12. Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J, Klotsas A, Matika R, Xiao X, Franks R, Heidenreich KA, Sajan MP, Farese RV, Stolz DB, Tso P, Koo SH, Montminy M, Unterman TG. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006;281:10105–10117. [PubMed]
13. Samuel VT, Choi CS, Phillips TG, Romanelli AJ, Geisler JG, Bhanot S, McKay R, Monia B, Shutter JR, Lindberg RA, Shulman GI, Veniant MM. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes. 2006;55:2042–2050. [PubMed]
14. Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D, Dong H. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab. 2003;285:E718–E728. [PubMed]
15. Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003;44:22–32. [PubMed]
16. Kamagate A, Qu S, Perdomo G, Su D, Kim DH, Slusher S, Meseck M, Dong HH. FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. J Clin Invest. 2008;118:2347–2364. [PMC free article] [PubMed]• This report establishes Mttp as a Foxo1 target.
17. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, Unterman TG, Carey MC, Kahn CR. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008;14:778–782. [PMC free article] [PubMed]• This study defines the mechanisms by which hepatic insulin resistance increases susceptibility to cholesterol gallstones.
18. Graf GA, Yu L, Li WP, Gerard R, Tuma PL, Cohen JC, Hobbs HH. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem. 2003;278:48275–48282. [PubMed]
19. Yu L, Gupta S, Xu F, Liverman AD, Moschetta A, Mangelsdorf DJ, Repa JJ, Hobbs HH, Cohen JC. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2005;280:8742–8747. [PubMed]
20. Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS, Horton JD. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest. 1997;100:2115–2124. [PMC free article] [PubMed]
21. Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, Kasuga M. Role of the insulin receptor substrate 1 and phosphatidylinositol 3- kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes. 2002;51:1672–1680. [PubMed]
22. Dong XC, Copps KD, Guo S, Li Y, Kollipara R, DePinho RA, White MF. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab. 2008;8:65–76. [PMC free article] [PubMed]• This study shows the important role played by Foxo1 in mediating the effects of insulin resistance on glucose homeostasis.
23. Taniguchi CM, Kondo T, Sajan M, Luo J, Bronson R, Asano T, Farese R, Cantley LC, Kahn CR. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 2006;3:343–353. [PubMed]
24. Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K, Hayashi Y, Iguchi H, Matsuki Y, Hiramatsu R, Shimano H, Yamada N, Ohno S, Kasuga M, Noda T. PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J Clin Invest. 2003;112:935–944. [PMC free article] [PubMed]
25. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, Schulze A. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 2005;24:6465–6481. [PubMed]
26. Ono H, Shimano H, Katagiri H, Yahagi N, Sakoda H, Onishi Y, Anai M, Ogihara T, Fujishiro M, Viana AY, Fukushima Y, Abe M, Shojima N, Kikuchi M, Yamada N, Oka Y, Asano T. Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. Diabetes. 2003;52:2905–2913. [PubMed]
27. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000;14:2819–2830. [PubMed]
28. Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS. Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc Natl Acad Sci U S A. 2003;100:3155–3160. [PubMed]
29. Kotzka J, Muller-Wieland D, Koponen A, Njamen D, Kremer L, Roth G, Munck M, Knebel B, Krone W. ADD1/SREBP-1c mediates insulin-induced gene expression linked to the MAP kinase pathway. Biochem Biophys Res Commun. 1998;249:375–379. [PubMed]
30. Kim KH, Song MJ, Yoo EJ, Choe SS, Park SD, Kim JB. Regulatory role of glycogen synthase kinase 3 for transcriptional activity of ADD1/SREBP1c. J Biol Chem. 2004;279:51999–52006. [PubMed]
31. Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, Ericsson J. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7) Cell Metab. 2005;1:379–391. [PubMed]
32. Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest. 1997;99:846–854. [PMC free article] [PubMed]
33. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–1131. [PMC free article] [PubMed]
34. Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem. 2002;277:9520–9528. [PubMed]
35. Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem. 2002;277:19353–19357. [PubMed]
36. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Molecular Cell. 2000;6:87–97. [PubMed]
37. Fisher SJ, Kahn CR. Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J Clin Invest. 2003;111:463–468. [PMC free article] [PubMed]
38. Biddinger SB, Hernandez-Ono A, Rask-Madsen C, Haas JT, Aleman JO, Suzuki R, Scapa EF, Agarwal C, Carey MC, Stephanopoulos G, Cohen DE, King GL, Ginsberg HN, Kahn CR. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 2008;7:125–134. [PubMed]• This work defines the mechanisms by which hepatic insulin resistance may contribute to dyslipidemia and atherosclerosis.
39. Sparks JD, Sparks CE. Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Biochim Biophys Acta. 1994;1215:9–32. [PubMed]
40. Fisher EA, Pan M, Chen X, Wu X, Wang H, Jamil H, Sparks JD, Williams KJ. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways. J Biol Chem. 2001;276:27855–27863. [PubMed]
41. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–489. [PubMed]
42. Shaffer EA, Small DM. Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity. J Clin Invest. 1977;59:828–840. [PMC free article] [PubMed]
43. Bennion LJ, Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest. 1975;56:996–1011. [PMC free article] [PubMed]
44. Kubota N, Kubota T, Itoh S, Kumagai H, Kozono H, Takamoto I, Mineyama T, Ogata H, Tokuyama K, Ohsugi M, Sasako T, Moroi M, Sugi K, Kakuta S, Iwakura Y, Noda T, Ohnishi S, Nagai R, Tobe K, Terauchi Y, Ueki K, Kadowaki T. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab. 2008;8:49–64. [PubMed]• This article provides compelling data that insulin signals primarily through IRS-1 in the fed state, but through IRS-2 in the fasted state. This suggests that these two proteins, which have largely been considered redundant, may in fact have distinct roles in insulin signaling.
45. Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn CR. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Diabetes. 2005;54:1314–1323. [PubMed]
46. Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O'Rahilly S, Savage DB. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009;119:315–322. [PMC free article] [PubMed]• This important study in humans characterizes the effects of mutations in the insulin receptor and its downstream target, AKT2, on serum and hepatic triglyceride levels.
47. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7:95–96. [PubMed]
48. Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty acid regulation of hepatic gene transcription. J Nutr. 2005;135:2503–2506. [PubMed]
49. Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Tomita S, Sekiya M, Hasty A, Nakagawa Y, Sone H, Toyoshima H, Ishibashi S, Osuga J, Yamada N. Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes. 2004;53:560–569. [PubMed]
50. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L, Kunos G. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298–1305. [PMC free article] [PubMed]
51. Kakuma T, Lee Y, Higa M, Wang Z, Pan W, Shimomura I, Unger RH. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci U S A. 2000;97:8536–8541. [PubMed]