Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin’s control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway.

This review describes the signaling pathways involved in the regulation of liver metabolism by insulin. In addition, it explores the molecular mechanisms underlying hepatic insulin resistance, highlighting the contribution of intrahepatic and extrahepatic pathways.

Metabolic disorders such as obesity and type II diabetes mellitus (T2DM) have reached epidemic proportions and continue to be a leading cause of death worldwide.The liver plays a central role in the systemic regulation of glucose and lipid metabolism and aberrant hepatic insulin action is thought to be a primary driver of insulin resistance, in which higher circulating insulin levels are necessary to adequately control blood glucose levels. During a normal physiologic fasting period, a high glucagon-to-insulin ratio decreases the rate of glucose consumption and shifts the liver to glucose production, first by consuming its stores of glycogen (glycogenolysis) and then from glucogenic precursors in a synthetic pathway (gluconeogenesis).In the postprandial state, decreasing glucagon and increasing insulin levels signal the liver to increase glucose consumption, stop glucose production, and store excess nutrients in the form of glycogen and lipids.In pathologic states, such as obesity and T2DM, insulin fails to appropriately regulate hepatic metabolism, leading to excess production of glucose despite accelerated rates of lipid synthesis, a condition now commonly referred to as selective hepatic insulin resistance.As a consequence, insulin-resistant disorders such as obesity and T2DM are closely linked to nonalcoholic fatty liver disease (NAFLD), a disorder that can lead to liver dysfunction and progress to deadly nonalcoholic steatohepatitis.

Increased rates of glucose production and lipogenesis are well documented in insulin-resistant human beings. Patients with NAFLD almost universally show hyperinsulinemia.In addition, both obese and diabetic human beings show a higher prevalence of NAFLD than lean ones.Isotope labeling experiments in subjects with NAFLD showed that subjects with increased hepatic steatosis had 2-fold higher rates of de novo lipogenesis and increased plasma levels of free fatty acids (FFAs) and insulin.In addition to increased lipid synthesis, insulin-resistant individuals have increased rates of hepatic glucose production (HGP).Indeed, there is a significant correlation between rates of gluconeogenesis and the extent of liver fat in NAFLD patients.Therefore, during the progression of insulin resistance, insulin fails to suppress HGP yet continues to drive excess lipid synthesis, leading to the sequela of NAFLD, hyperglycemia, and hypertriglyceridemia.

Experiments in both mice and human beings have shown the essential role for hepatic insulin action in the regulation of glucose production and lipogenesis. Liver insulin resistant knockout mice (LIRKO) mice fail to inhibit glucose production and cannot induce de novo lipogenesis.In addition, LIRKO mice fail to accumulate lipids and do not develop fatty liver, even when fed a high-fat diet, despite increased blood glucose and insulin levels.These liver-specific knockout mouse models resemble human beings that lack a functioning insulin receptor and show extremely high blood glucose levels, however, hepatic steatosis fails to arise. The clinical findings corroborate the concept that the liver is the key driver of insulin’s whole-body action on glucose and lipid homeostasis.Further supporting this statement, fat-specific deletion of the insulin receptor results in lipodystrophy along with insulin resistance and hyperglycemia.However, these mice are not protected from NAFLD, and eventually develop nonalcoholic steatohepatitis, unlike the LIRKO mice and human beings with insulin-receptor mutations. Experiments using congenital mouse models can pose some issues because off-target effects of genetic manipulation can develop over time and obscure results. For example, LIRKO mice are typically smaller than wild-type mice, possibly because of defects in the insulin-like growth factor axis, and eventually the observed effects, such as hyperglycemia, disappear as a result of liver failure.In these instances, inducible genetic knockouts hold some benefit because one can observe the direct effects of the knockout before the off-target effects begin to manifest. In this case, inducible knockout of the insulin receptor reciprocates the glucose intolerance and hyperinsulinemia of the LIRKO mice without the off-target metabolic effects. These mice also fail to promote hepatic lipogenesis in response to a high carbohydrate meal.Resolving what specific factors mediate insulin action on the liver to generate these paradoxical effects has become a major focus in obesity and T2DM studies and has provided many insights into the molecular mechanisms of insulin action and hepatic metabolism. Here, we discuss these pathways in depth and suggest an integrated model to deconvolute the paradox of hepatic insulin action that integrates the direct effects of insulin action on the liver with many extrahepatic pathways from peripheral metabolic organs.

Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.

Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.

Hepatic Insulin Signaling and Lipid Metabolism

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Birnbaum M.J. Akt2 is required for hepatic lipid accumulation in models of insulin resistance. 31 Lu M.

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Birnbaum M.J. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. , 32 Titchenell P.M.

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Birnbaum M.J. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. Figure 1 PI3K/Akt signaling in hepatocytes. Insulin binds to and activates the insulin receptor on the liver surface after a meal. After activation, the receptor recruits and activates IRS, which then activates PI3K. PI3K phosphorylates the signaling lipid molecule PIP 2 into PIP 3 in a process that is opposed by PTEN. PIP 3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which phosphorylates Akt at Thr308. To fully activate Akt, mTORC2 also must phosphorylate it at Ser473. From Akt, different pathways for controlling glucose and lipid homeostasis branch out. Glycogen synthesis is induced through Akt inhibition of GSK3. In addition, Akt can promote glycogen synthesis in a manner independent of GSK3, such as activation of GYS2 by glucose-6-phosphate (G6P). Akt inhibition of TSC activates mTORC1, which in turn activates the lipogenic gene program through activation of SREBP1c and Gck, which phosphorylates glucose to G6P, which feeds into glycolysis and glycogen synthesis. In addition, G6P activates ChREBP, which activates lipogenesis along with SREBP1c. Akt inhibits FoxO1, resulting in an inhibition of gluconeogenesis by suppressing expressing of the proteins glucose-6-phosphatase (G6pc) and Pck1. Externally, FFAs can promote gluconeogenesis and contribute to insulin resistance by being taken up by the liver and converted to Acetyl-CoA, which activates pyruvate carboxylase. Strong evidence has indicated that the phosphoinositide-3-phosphate kinase (PI3K)/Akt pathway is the key signaling pathway that mediates the effects of insulin on anabolic metabolism in all organisms.When insulin binds to the insulin receptor (IR), it recruits and activates PI3K through insulin-receptor substrates (IRS), generating phosphatidylinositol (3,4,5)-trisphosphate (PIP). IRS proteins link the PI3K pathway to the insulin receptor by binding to phosphotyrosine residues on the insulin receptor.Knockout of multiple insulin-receptor substrates prevents activation of the pathway in response to insulin, leading to insulin resistance and hyperglycemia, but not hepatic steatosis.PIPinitiates recruitment of Akt (named as such when it was discovered to be the oncogene responsible for thymoma in Ak mice, also called protein kinase B) and activates it through 3-phosphoinositide-dependent protein kinase 1 via phosphorylation of Thr308 on Akt Figure 1 ). Hepatic PI3K deletion in mice prevents steatosis; however, the mice still show significant glucose intolerance, hyperinsulinemia, and impaired Akt activity.In addition, deficiency in 3-phosphoinositide-dependent protein kinase 1 in mouse liver causes glucose intolerance and results in liver failure.Opposing the action of PI3K, phosphatase and tensin homolog (PTEN) dephosphorylates PIP, rendering it inactive ( Figure 1 ). In vivo deletion of PTEN results in substantial lipid accumulation in the liver.Studies have shown that deletion of Akt2 is sufficient to prevent lipid accumulation in livers with PTEN also removed,suggesting that Akt serves as the essential downstream signaling kinase. Full activation of Akt also requires an additional phosphorylation by mechanistic target of rapamycin complex 2 (mTORC2) at Ser473 Figure 1 ). Of the 3 isoforms of Akt, Akt2 (protein kinase B β) plays the most substantial role in metabolic regulation because mice with germline deletion of Akt2 show insulin resistance and a diabetes-like phenotype.Mice lacking hepatic Akt2, the most abundant hepatic isoform, have decreased lipid accumulation, and decreased de novo lipogenesis in the liver of ob/ob mice or mice subjected to a high-fat diet.However, despite its abundance, liver-specific deletion of Akt2 only results in mild insulin resistance owing to residual Akt1 activity. Knockout of both Akt1 and 2 is necessary to fully suppress Akt activity in the liver and leads to severe insulin resistance, glucose intolerance, and a reduction in hepatic lipid synthesis.

33 Menon S.

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Manning B.D. Spatial control of the TSC complex integrates insulin and nutrient regulation of mtorc1 at the lysosome. 34 Howell J.J.

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Manning B.D. A growing role for mTOR in promoting anabolic metabolism. 35 Schwarz J.M.

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Birnbaum M.J. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. , 37 Wan M.

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Birnbaum M.J. Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. 38 Yecies J.L.

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Manning B.D. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Because several studies support an obligate role of hepatic insulin action to regulate lipid metabolism, defining the mechanisms downstream of Akt are essential for understanding the pathogenesis of NAFLD during insulin resistance. One major downstream target of Akt is the mechanistic target of rapamycin complex 1 (mTORC1). Akt activates mTORC1 through inhibition of the tuberous sclerosis complex (TSC), a protein that inhibits mTORC1 localization to and activation at the lysosome through inhibition of Rheb Figure 1 ). Activation of mTORC1 shifts the cell from a catabolic to an anabolic and proliferative state in which protein, lipid, and nucleic acid synthesis become greatly enhanced.Because one of the hallmarks of T2DM and insulin resistance is enhanced de novo lipogenesis,research has focused on determining the role of mTORC1 in de novo lipogenesis and hepatic lipid metabolism. Studies have shown that activation of mTORC1 is required for de novo lipogenesis, however, activation of mTORC1 alone is not sufficient to induce lipogenesis in the absence of hepatic insulin signaling.This is consistent with the phenotype of mice lacking Tsc specifically in hepatocytes because liver-specific TSC knockout fails to induce lipogenesis and lipogenic gene expression despite constitutive mTORC1 signaling, suggesting Akt regulates hepatic lipid metabolism via mTORC1-dependent and -independent pathways.

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Manning B.D. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. , 40 Düvel K.

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Manning B.D. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. 41 Owen J.L.

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Brown M.S. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. 42 Shimomura I.

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Horton J.D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. , 43 Moon Y.A.

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Horton J.D. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. 44 Brown M.S.

Goldstein J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. 45 Matsuda M.

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Shimomura I. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. 43 Moon Y.A.

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Horton J.D. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Sterol regulatory element binding protein 1c (SREBP1c) is a member of the SREBP class of transcription factors that are key players in controlling cellular expression of genes required for lipid and cholesterol metabolism.Insulin regulates SREBP1c by both enhancing its gene expression and post-translational processing. Akt mediates these processes through multiple downstream pathways. mTORC1, in particular, is a key activator of SREBP1c because inhibiting mTORC1 blocks insulin-dependent cleavage and activation of SREBP1c Figure 1 ). For example, SREBP1c processing in transgenic rats requires S6K1, a target of mTORC1.Consistent with increased lipogenesis in insulin-resistant models, several models for diabetes in mice, such as ob/ob, involve heightened levels of SREBP1c activity.SREBP cleavage-activating protein (SCAP) is a major regulator of SREBP activity because it chaperones SREBP proteins from the endoplasmic reticulum to the Golgi where it is cleaved, releasing the active part of SREBP to the nucleus where it regulates transcription.SCAP is required for activation of all isoforms of SREBP and its deletion significantly reduces cholesterol and fatty acid synthesis in the liver.In addition, eliminating SCAP specifically in hepatocytes reduces lipid accumulation in the liver and is sufficient to prevent hepatic steatosis in ob/ob mice and sucrose-fed hamsters.Therefore, SREBP1c is a necessary factor in lipogenic gene expression and in the development of fatty liver.

46 Dentin R.

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Ferré P. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. 47 Iizuka K.

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Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. 48 Iizuka K.

Miller B.

Uyeda K. Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice. 49 Benhamed F.

Denechaud P.D.

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Postic C. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. 50 Hurtado Del Pozo C.

Vesperinas-García G.

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Corripio-Sánchez R.

Torres-García A.J.

Obregon M.J.

Calvo R.M. ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity. 51 Jois T.

Chen W.

Howard V.

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Chan L.

Cowley M.A.

Sleeman M.W. Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice. 52 Linden A.G.

Li S.

Choi H.Y.

Fang F.

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Uyeda K.

Hammer R.E.

Horton J.D.

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Liang G. Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. In addition to SREBP1c, carbohydrate response element binding protein (ChREBP) is a well-studied, glucose-responsive transcription factor that may play a role in controlling hepatic lipid metabolism. Glucose-6-phosphate is the key activator of ChREBP, facilitating its migration to the nucleus Figure 1 ). Because insulin signaling enhances glucose uptake in the liver, ChREBP becomes activated. As a transcription factor, ChREBP activates similar lipogenic genes to SREBP1c, although its roles in insulin sensitivity remain controversial. Normal mice with ChREBP deleted globally show decreased lipogenesis as well as mild insulin resistance.However, ChREBP deficiency in obese mice also results in decreased lipid accumulation and improved insulin sensitivity.Moreover, increased ChREBP is sufficient to increase fatty liver progression because overexpression of hepatic ChREBP in mice results in steatosis.Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbohydrate diet, but had no effect on lipogenesis and lipogenic gene expression under normal chow.Hepatic deletion of ChREBP in mice following a high-carbohydrate diet caused a reduction in glycolytic and lipogenic gene expression, including a partial loss of SREBP1c expression. Restoration of nuclear SREBP1c signaling in liver-specific ChREBP knockout mice increased the expression of the lipogenic genes ACLY, ACC2, SCD1, and GPAT, but failed to restore them to control levels, suggesting that both SREBP1c and ChREBP are needed to fully regulate lipogenesis in the liver. In addition, SREBP1c overexpression had no effect on restoring glycolytic gene expression. Moreover, overexpressing ChREBP was not sufficient to regain any significant lipogenic gene induction in mice lacking SREBP after SCAP deletion, showing that SREBP is required for the induction of lipogenic expression.The interplay between ChREBP and SREBP1c in regulating lipogenic gene expression helps ensure that the liver does not initiate lipid synthesis unless both glucose and insulin are present, and future studies will continue to unravel their coordinated regulation of lipid synthesis.

53 Poulsen M.K.

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Pedersen S.B.

Grønbæk H.

Nielsen S. Impaired insulin suppression of VLDL-triglyceride kinetics in nonalcoholic fatty liver disease. , 54 Lewis G.F.

Uffelman K.D.

Szeto L.W.

Steiner G. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL ApoB production in normal weight and obese individuals. 55 Ginsberg H.N.

Zhang Y.-L.

Hernandez-ono A. Metabolic syndrome : focus on dyslipidemia. 56 Steiner G.

Haynes F.J.

Yoshino G.

Vranic M. Hyperinsulinemia and in vivo very-low-density lipoprotein-triglyceride kinetics. 57 Han S.

Liang C.P.

Westerterp M.

Senokuchi T.

Welch C.L.

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Accili D.

Tall A.R. Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice. 58 Quinn W.J.

Wan M.

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Birnbaum M.J.

Titchenell P.M. MTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion. Alongside de novo lipogenesis, insulin action also regulates lipid homeostasis by regulating triacylglycerol (TAG) secretion from the liver via very-low-density lipoprotein (VLDL)-TAG export. Enhanced secretion of VLDL-TAG is another hallmark of people with insulin-resistant conditions, such as obesity or NAFLD.In particular, a failure of insulin to facilitate degradation of apolipoprotein B, a major protein in VLDL synthesis, as well as increased levels of FFAs and increased lipogenesis in insulin-resistant disorders, are believed to stimulate VLDL secretion.The last point potentially carries the most weight because it may not be insulin resistance per se that stimulates VLDL secretion, but instead the hyperinsulinemia that results from it. Studies in rats have shown that hyperinsulinemia stimulates TAG turnover and VLDL secretion.In addition, disrupting insulin signaling in mouse livers by deleting Akt or the insulin receptor reduces VLDL secretion.Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial part of VLDL synthesis and secretion.As such, insulin regulation of VLDL-TAG secretion is complex and the coordinated control of apolipoproteins, phospholipids, and TAG synthesis are essential for proper control of VLDL-TAG secretion.