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Curr Opin Clin Nutr Metab Care. Author manuscript; available in PMC May 21, 2012.
Published in final edited form as:
PMCID: PMC3356999
NIHMSID: NIHMS376288
Fatty acid regulation of hepatic lipid metabolism
Donald B. Jump
Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA
Correspondence to Donald B. Jump, PhD, 107A Milam Hall, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA, Tel: +1 541 737 4007; Donald.jump/at/oregonstate.edu
Purpose of review
To discuss transcriptional mechanisms regulating hepatic lipid metabolism.
Recent findings
Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20–22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20–22 PUFAs on disease progression in humans is not fully understood, studies with mice have provided clues suggesting that impaired PUFA metabolism may contribute to the severity of risk factors associated with NIDDM and MetS. High fat diets promote hyperglycemia, insulin resistance and fatty liver in C57BL/6J mice, an effect that correlates with suppressed expression of enzymes involved in PUFA synthesis and decreased hepatic C20–22 PUFA content. A/J mice, in contrast, are resistant to diet-induced obesity and diabetes; these mice have elevated expression of hepatic enzymes involved in PUFA synthesis and C20–22 PUFA content. Moreover, loss-of-function and gain-of-function studies have identified fatty acid elongase (Elovl5), a key enzyme involved in PUFA synthesis, as a regulator of hepatic lipid and carbohydrate metabolism. Elovl5 activity regulates hepatic C20–22 PUFA content, signaling pathways (Akt and PP2A) and transcription factors (SREBP-1, PPARα, FoxO1 and PGC1α) that control fatty acid synthesis and gluconeogenesis.
Summary
These studies may help define novel strategies to control fatty liver and hyperglycemia associated with NIDDM and MetS.
Keywords: fatty acid elongation, fatty acid synthesis and oxidation, fatty liver, FoxO1, gluconeogenesis, VLDL metabolism
Dietary fat is an essential component in the human diet, but too much fat or an imbalance of the type of fat can have negative effects on health and well-being [1••]. Chronic consumption of excessive calories coupled with physical inactivity promotes obesity, diabetes and metabolic syndrome [2••]. Obesity is associated with excessive ectopic deposition of fat in tissues, such as heart, β-cell, liver and adipose, leading to lipotoxicity and inflammation [3]. The accumulation of lipid in liver, that is, hepatosteatosis, leads to nonalcoholic fatty liver disease, a growing health problem in the obese population and more severe liver diseases such as nonalcoholic steatohepatitis, fibrosis, cirrhosis and cancer [4•]. Although excessive saturated fat (SFA) consumption promotes lipid storage and inflammation, dietary polyunsaturated fatty acids (PUFAs) play a protective role by controlling synthesis and oxidation of SFA and monounsaturated fatty acid (MUFA), lower hepatic fat content [5] and improve blood lipid profiles associated with risk of cardiovascular disease [1••,6]. The goal of this article is to highlight recent studies implicating fatty acid synthesis as a target for controlling the severity of risk factors associated with diabetes (NIDDM) and metabolic syndrome (MetS).
Expression of the enzymes involved in de novo lipogenesis (DNL) (ACC1, FASN) and MUFA synthesis (SCD1 and Elovl6) synthesis are coordinately controlled during fasting and refeeding, and by insulin, dietary carbohydrate and dietary fat (Fig. 1) [7,8]. This coordinate regulation is due, at least in part, to the hormonal and nutrient control of key transcription factors regulating the expression of these enzymes. These transcription factors include SREBP-1 and the ChREBP/MLX, LXR/RXR and PPARα/RXR heterodimers (Table 1) [5]. Insulin induces SREBP-1 nuclear abundance through several mechanisms, including increased transcription of the SREBP-1c gene, stabilization of SREBP-1 mRNA and protection of nuclear (mature) SREBP-1 from 26S proteasomal degradation. Feeding mice high fat diets containing predominately saturated fat for a short duration (24–28 h) induces SREBP-1 nuclear abundance and its co-activation by PGC1β. Elevated nuclear content of SREBP-1 induces DNL, MUFA and triglyceride synthesis and storage [2••]. Long-term feeding (≥3 months) of high fat (lard) diets, however, has the opposite effect on SREBP-1 nuclear abundance and its target genes [8,9•]. This differential response can be linked to hepatic insulin resistance and elevated blood leptin and represents an adaption to the high fat diet [10]. Leptin suppresses SREBP-1 nuclear abundance and the expression of SREBP-1 target genes. Leptin also induces the phosphorylation of AMP-kinase (AMPK), which in turn phosphorylates acetyl CoA carboxylase (ACC) and lowers hepatic malonyl CoA (Table 2) [2••]. Malonyl CoA is a substrate for DNL and fatty acid elongation as well as an inhibitor of carnitine palmitoyl transferase-1 and β-oxidation [11].
Figure 1
Figure 1
Pathways for de-novo lipogenesis, monounsaturated and polyunsaturated fatty acid synthesis
Table 1
Table 1
Transcription factors inducing fatty acid synthesis, fatty acid elongation and desaturation
Table 2
Table 2
Impact of obesity and diabetes on hepatic expression of enzymes involved in fatty acid synthesis, elongation and desaturation
High carbohydrate–low fat diets induce DNL and MUFA synthesis but diets supplemented with PUFAs (ω3 or ω6 PUFAs) suppress SREBP-1 nuclear abundance and the expression of genes involved in DNL and MUFA synthesis. Of the PUFAs examined, docosahexaneoic acid (C22 : 6, ω3, DHA) is amongst the most robust suppressors of nuclear SREBP-1; DHA counters many of the effects of insulin on SREBP-1 but does not induce insulin resistance. This is achieved through effects on SREBP-1c gene transcription, SREBP-1 mRNA turnover and a 26S proteasome-dependent and Erk-dependent mechanism that accelerate the degradation of the mature form of SREBP-1 [5].
High carbohydrate–low fat diets also induce the accumulation of carbohydrate response element binding protein (ChREBP) in the nucleus. ChREBP along with its heterodimer partner max-like factor-X (MLX) control the expression of multiple genes (Glut2, L-PK, ACC, FASN, SCD1 and Elovl6) involved in DNL and MUFA synthesis [12]. ChREBP binding to DNA requires MLX as a heterodimer partner. Dietary PUFAs suppress the nuclear content of both ChREBP and MLX nuclear abundance leading to a decline in expression of ChREBP/MLX target genes [5].
The LXR/RXR heterodimer is a major regulator of lipogenic gene expression through direct interaction with the promoters of these genes as well as inducing SREBP-1c gene transcription. Activation of LXR by high dietary cholesterol, oxysterols or other agonists elevates nuclear content of SREBP-1 and increases DNL and MUFA synthesis leading to hyperlipidemia [13]. Some investigators have reported effects of fatty acids on LXR function [14], whereas others have found little effect of dietary PUFAs on LXR target genes (ABCA1, ABCG5, ABCG8 and CYP7A) in vivo [5].
PPARα, PPARβ/δ, PPARγ1 and PPARγ2 are fatty acid-activated nuclear receptors that respond to changes in intracellular fatty acid content [15]. In primary hepatocytes, however, the response of PPARα to various fatty acids is not uniform. Eicosapentaenoic acid (C20 : 5, ω3, EPA) is a robust activator of PPARα, whereas SFA, MUFA and other ω3 and ω6 PUFAs are weak regulators of PPARα [5]. PPARα is a major regulator of genes involved in mitochondrial, peroxisomal and microsomal fatty acid oxidation as well as genes involved in gluconeogenesis through its regulation of PGC1α and FGF21 [16•,17]. Moreover, PPARα is a major drug target for treating severe hyperlipidemia. When compared to pharmaceutical agonists, however, EPA is a weak activator of PPARα [5].
Elevated DNL and esterification of fatty acids into triglycerides contributes to the elevation of plasma triglycerides seen in MetS. Elevated plasma triglycerides are an independent risk factor for cardiovascular disease [18•20•]. Hepatic production of VLDL is governed by availability of substrate (TAG) and apolipoproteins required for VLDL assembly, such as apoB. Dietary C20–22 ω3 PUFAs inhibit VLDL secretion by inhibiting DNL, enhancing fatty acid oxidation, and promoting apoB degradation [21,22,23•,24].
Ablation or overexpression of enzymes involved in DNL, that is, acetyl CoA carboxylase (ACC1 and ACC2) [25•], fatty acid synthase (FASN) [26] or MUFA synthesis, that is, stearoyl CoA desaturase-1 (SCD1) [27] or fatty acid elongase-6 (Elovl6) [28], significantly affects the severity of diet-induced hyperglycemia, dyslipidemia and fatty liver. Ntambi’s group [27] was the first to report that mice lacking SCD1 are protected against diet-induced and genetically induced obesity, fatty liver, hypertriglyceridemia and insulin resistance. More recently, Brown et al. [29•] used an antisense oligonucleotide approach to suppress SCD1 expression in LDLR−/−, ApoB100/100 mice, a model of hyperlipidemia and atherosclerosis. Although suppression of SCD1 protects mice from diet-induced obesity, insulin resistance and fatty liver, this treatment induced aortic atherosclerosis. In a subsequent report, Rudel’s group combined the SCD1 antisense oligonucleotide approach with dietary ω3 PUFAs and prevented the symptoms of both MetS and atherosclerosis [30•]. Although these studies reveal the complexities associated with targeting a specific enzyme to manage risk factors associated with metabolic disease, they also offer a remedy by including dietary ω3 PUFA supplementation in the therapy regime.
Dietary PUFAs and in particular the C20–22 ω3 PUFAs are beneficial to human health and well-being by controlling lipid metabolism, blood lipids and inflammation [1••,3134]. Obese humans or patients with NIDDM or MetS, however, have low blood and tissue levels of C20–22 PUFAs; an effect usually attributed to impaired PUFA synthesis [4•,35•38•]. The metabolic basis and physiological consequences of low circulating and tissue levels of PUFAs in humans remain unclear. Studies on essential fatty acid deficiency and fatty acid desaturase-2 (FADS2, Δ6 desaturase) null mice make clear the necessity for dietary PUFAs and its conversion to ARA and DHA for the maintenance of multiple physiological processes and well-being [39•,40•,41].
The conversion of dietary precursors, linoleic acid and α-linolenic acids, to ARA and DHA requires fatty acid desaturases (FADS1, FADS2), fatty acid elongases (Elovl2 and Elovl5) and peroxisomal β-oxidation (Fig. 1) [5]. SREBP-1, PPARα, and HNF4α, but not ChREBP/MLX or LXR/RXR control the expression levels of these enzymes (Table 1). When compared with enzymes involved in DNL and MUFA synthesis, expression of these enzymes is less responsive to changes in blood insulin, fasting or refeeding (Table 2) [7,8]. Recent studies in mice have provided some clues as to the significance of changes in PUFA synthesis in the control of metabolic disease. In contrast to C57BL/6J mice, A/J mice are resistant to high fat diet-induced obesity, atherosclerotic lesions and fatty liver. Microarray analysis reveals elevated expression of enzymes involved in lipid metabolism, including those involved in peroxisome biogenesis and β-oxidation, fatty acid elongation (Elovl5) and desaturation (FADS1 and FADS2) [42•] in livers of A/J mice. Hall et al. [42•] linked the increased hepatic expression of these enzymes to elevated ARA levels in lysophosphatidylcholine and 2-arachidonylglycerol. These complex lipids are PPARα and cannabinoid receptor agonists, respectively. Moreover, proinflammatory cytokines (IL-1β and GSF) were lower in livers of A/J mice.
Livers of obese C57BL/6J mice fed high fat diets, however, have impaired PUFA synthesis as reflected by a low ratio of C20 : 4, ω6 to C18 : 2, ω6 and suppressed expression and activity of Elovl5. Interestingly, the expression of FADS1 or FADS2 was not affected by high fat (lard) diets [8]. Global ablation of Elovl5 lowers hepatic ARA and promotes fatty liver; an effect linked to the induction of nuclear SREBP-1 but not ChREBP [43]. In contrast, induction of hepatic Elovl5 activity, using a recombinant adenovirus approach, essentially abolished fatty liver in obese-diabetic mice [9•,44]. Although induction of hepatic Elovl5 activity did not elevate hepatic C20 : 4, ω6 levels, di-homo-γ-linolenic acid (C20 : 3, ω6) and adrenic acid (C22 : 4, ω6) were increased in livers of these mice [9•].
Hepatic steatosis is associated with low β-oxidation [4•] and low fasting blood levels of β-hydroxybutyrate [9•]. Increasing hepatic Elovl5 activity in obese mice restored β-hydroxybutyrate to normal levels suggesting that Elovl5 induced β-oxidation and ketogenesis. Because several targets of PPARα action were suppressed in livers of obese mice with elevated hepatic Elovl5 activity, Elovl5 may induce β-oxidation and ketogenesis through mechanisms independent of PPARα. The outcome of these studies establishes that: fatty acid elongases are regulated by diet; endogenous PUFA synthesis controls hepatic triglyceride content; and a change in elongase activity alone is sufficient to impact PUFA synthesis and hepatic triglyceride content. Similar studies using the FADS2 null mouse have not been reported but it is anticipated that FADS1 and FADS2 play equally important roles in controlling hepatic lipid metabolism and the onset of fatty liver and dyslipidemia.
Mice fed high fat (saturated) diets have fasting hyperglycemia due to increased hepatic glucose production and insulin resistance [45,46]. Hepatic glucose production during fasting is due to the induction of glycogenolysis and gluconeogenesis as well as the availability of gluconeogenic substrates [47•,48•]. Expression of enzymes involved in gluconeogenesis, that is, phosphoenolpyruvate carboxykinase (Pck1), pyruvate carboxylase (Pcx) and glucose-6 phosphatase catalytic unit (G6Pc), is controlled by several transcription factors (FoxO1, CREB, HNF4α, c/EBP and PPARα) and regulatory proteins (PGC1α, CBP, CRTC2, TRB3 and SIRT1) [46,49•,50,51]. CREB, CRTC2, FoxO1 and PGC1α have been identified as major regulators of Pck1 and G6Pc expression in fasting induced gluconeogenesis [46,52,53].
C57BL/6J mice fed high-fat diets develop fasting hyperglycemia, hyperinsulinemia and glucose intolerance [8,9•,45]. Hepatic nuclei of these mice have elevated levels of FoxO1, CRTC2 and PGC1α which induces expression of Pck1 and G6Pc. Livers of these obese diabetic mice have a low ratio of C20 : 4, ω6 to C18 : 2, ω6 and low activity of Elovl5 reflecting problems with PUFA synthesis. Inducing hepatic Elovl5 activity elevated hepatic C20–22 PUFAs and abrogates fasting hyperglycemia, hyperinsulinemia and glucose intolerance in these obese mice [9•]. Elevated Elovl5 activity attenuated Pck1 and G6Pc expression and suppressed nuclear content of FoxO1 and PGC1α but had no effect on the nuclear content of CREB, CRTC2, PPARα or HNF4α.
Nuclear levels of FoxO1 are regulated by controlling its phosphorylation and acetylation status [54•]. The serine–threonine kinase, Akt and the phosphatases, PP2A and MKP-3, control the phosphorylation status of FoxO1 [5557,58•]. Transcriptional co-activators with histone acetyl transferase activity, for example CREB-binding protein (CBP) and protein deacetylase activity, for example, sirtuins 1 (SIRT1), control the acetylation status of FoxO1 and PGC1α [54•,59]. The Elovl5-mediated decline in nuclear FoxO1 content was correlated with increased FoxO1 phosphorylation; phospho-FoxO1 is excluded from nuclei and degraded in the proteasome. Increased hepatic phospho-FoxO1 was correlated with elevated phosphorylation of Akt and the catalytic unit of PP2A. Phospho-Akt is an active kinase, whereas phosphorylation of PP2A catalytic unit inactivates PP2A phosphatase activity. Moreover, elevated Elovl5 activity suppressed hepatic levels of the Akt inhibitor, TRB3, but did not stimulate the phosphorylation of IRS2 or PDK1/2. The outcome of these studies indicates that elevation of hepatic Elovl5 activity maintains the phosphorylated form of FoxO1 during fasting, an event that lowers nuclear FoxO1 and suppresses expression of enzymes involved in gluconeogenesis. Similar studies investigating the effects of Elovl5 on the acetylation status of FoxO1 and PGC1α have not been reported. The outcome of these studies identified a novel link between hepatic carbohydrate metabolism and PUFA metabolism not seen with dietary C20–22 PUFAs.
Studies with genetically modified mice have established that enzymes involved in DNL and MUFA synthesis play an important role in controlling metabolism, gene expression and the onset and progression of diabetes and obesity. Recent studies with enzymes involved in PUFA synthesis indicate that these enzymes are equally important regulators of plasma and tissue fatty acid composition, signaling pathways controlling DNL, MUFA synthesis and gluconeogenesis. Although dietary PUFAs have well-established benefits to human health [1••], the studies discussed above indicate that controlling PUFA synthesis may provide additional health benefits not seen with dietary PUFAs alone.
Acknowledgements
This project was supported by the National Institutes of Health Grant DK43220 and the United States Department of Agriculture, National Institute for Food and Agriculture Grant 2009-65200-05846. The author thanks Drs Philip C. Calder, Richard Deckelbaum, William S. Harris and Penny Kris-Etherton for their helpful comments and enthusiastic support.
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 213–214).
1. Harris WS, Mozaffarian D, Rimm E, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism Council on Cardiovascular Nursing Council on Epidemiology and Prevention. Circulation. 2009;119:902–907. [PubMed] This article provides recommendations to increase dietary PUFAs to 5–10% of total energy to reduce the risk cardiovascular disease.
2. Unger RH, Scherer PE Gluttony, sloth and the metabolic syndrome: a road map to lipotoxicity. Trends Endocrinol Metab. 2010;21:345–352. [PubMed] This excellent review discusses diet, lifestyle and the metabolic and molecular basis of ectopic lipid deposition and lipotoxicity.
3. Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. 2008;8:923–934. [PMC free article] [PubMed]
4. Tiniakos DG, Vos MB, Brunt EM Nonalcoholic fatty liver disease: pathology and pathogenesis. Ann Rev Pathol Mech Dis. 2010;5:145–171. [PubMed] This is an up-to-date and comprehensive review of factors contributing to fatty liver diseases.
5. Jump DB. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol. 2008;19:242–247. [PMC free article] [PubMed]
6. Harris WS, Miller M, Tighe AP, et al. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis. 2008;197:12–24. [PubMed]
7. Wang Y, Botolin D, Christian B, et al. Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases. J Lipid Res. 2005;46:706–715. [PMC free article] [PubMed]
8. Wang Y, Botolin D, Xu J, et al. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J Lipid Res. 2006;47:2028–2041. [PMC free article] [PubMed]
9. Tripathy S, Torres-Gonzalez M, Jump DB Elevated hepatic fatty acid elongase-(Elovl5) activity corrects dietary fat induced hyperglycemia in obese C57BL/6J mice. J Lipid Res. 2010;51:2642–2654. [PubMed] This study demonstrates the increased activity of the fatty acid elongase-5 in livers of obese diabetic mice abrogates fasting hyperglycemia and fatty liver.
10. Jiang L, Wang Q, Yu Y, et al. Leptin contributes to the adaptive response of mice to high fat diet intake through suppressing the lipogenic pathway. PloS One. 2009;4:e6884, 1–9. [PMC free article] [PubMed]
11. Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr. 2008;28:253–272. [PubMed]
12. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006;4:107–110. [PubMed]
13. Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–2838. [PubMed]
14. Howell G, 3rd, Deng X, Yellaturu C, et al. N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced transactivating capacity of LXRα Biochim Biophys Acta. 2009;1791:1190–1196. [PMC free article] [PubMed]
15. Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 1999;3:397–403. [PubMed]
16. Kliewer SA, Mangelsdorf DJ Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr. 2010;91:254S–257S. [PubMed] This excellent review discusses FGF21 as a target for PPARα regulation and as a regulator of PGC1α, hepatic gluconeogenesis, fatty acid oxidation and ketogenesis.
17. Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–425. [PubMed]
18. Kannel WB, Vasan RS Triglycerides as vascular risk factors: new epidemiologic insights. Curr Opin Cardio. 2009;24:345–350. [PMC free article] [PubMed] A key documentation on the triglycerides as independent risk factors for cardiovascular disease.
19. Morrison A, Hokanson JE The independent relationship between triglycerides and coronary heart disease. Vas Health Risk Manage. 2009;5:89–95. [PMC free article] [PubMed] A key documentation on the triglycerides as independent risk factors for cardiovascular disease.
20. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91:502–509. [PubMed] A key documentation on the triglycerides as independent risk factors for cardiovascular disease.
21. Fisher EA, Williams KJ. Autophagy of an oxidized, aggregated protein beyond the ER: a pathway for remarkably late-stage quality control. Autophagy. 2008;4:721–723. [PubMed]
22. Brodsky JL, Fisher EA. The many intersecting pathways underlying apolipo-protein B secretion and degradation. Trends Endocrinol Metab. 2008;19:254–259. [PMC free article] [PubMed]
23. Ginsberg HN, Fisher EA The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res. 2009;50:S162–S166. [PubMed] This is an excellent review on the role apoB plays in the control of VLDL assembly and secretion and the mechanisms controlling apoB metabolism.
24. Jump DB, Botolin D, Wang Y, et al. Docosahexaenoic acid (DHA) and hepatic gene transcription. Chem Phys Lipids. 2008;153:3–13. [PMC free article] [PubMed]
25. Wakil SJ, Abu-Elheiga LA Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50(Suppl):S138–S143. [PubMed] In this review article, the authors suggest acetyl CoA carboxylase subtypes may be prospective therapeutic targets to combat human diseases like obesity, diabetes, cancer and cardiovascular complications.
26. Chakravarthy MV, Pan Z, Zhu Y, et al. ‘New’ hepatic fat activates PPARαto maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005;1:309–322. [PubMed]
27. Ntambi JM, Miyazaki M, Stoehr JP, et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A. 2002;99:11482–11486. [PubMed]
28. Matsuzaka T, Shimano H, Yahagi N, et al. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med. 2007;13:1193–1202. [PubMed]
29. Brown JM, Chung S, Sawyer JK, et al. Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation. 2008;118:1467–1475. [PubMed] The authors used an antisense oligonucleotide approach to knockdown SCD1 activity in vivo; they reported adverse consequences in mice with suppressed SCD1 activity.
30. Brown JM, Chung S, Sawyer JK, et al. Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30:24–30. [PubMed] The study reports that the combined therapy of SCD1 antisense oligonucleotide and dietary fish oil supplementation abrogates both atherosclerosis and metabolic syndrome.
31. Harris WS. N-3 long-chain polyunsaturated fatty acids reduce risk of coronary heart disease death: extending the evidence to the elderly. Am J Clin Nutr. 2003;77:279–280. [PubMed]
32. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–2757. [PubMed]
33. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82–96. [PubMed]
34. Lichtenstein AH, Appel LJ, Brands M, et al. Summary of American Heart Association Diet and Lifestyle Recommendations revision 2006. Arterioscler Thromb Vasc Biol. 2006;26:2186–2191. [PubMed]
35. Warensjo E, Rosell M, Hellenius ML, et al. Associations between estimated fatty acid desaturase activities in serum lipids and adipose tissue in humans: links to obesity and insulin resistance. Lipids Health Dis. 2009;8:37. [PubMed] One of the many articles citing low PUFAs in blood and tissues in humans with diabetes, obesity or metabolic syndrome.
36. Sjogren P, Sierra-Johnson J, Gertow K, et al. Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance. Diabetologia. 2008;51:328–335. [PubMed] One of the many articles citing low PUFAs in blood and tissues in humans with diabetes, obesity or metabolic syndrome.
37. Kotronen A, Seppanen-Laakso T, Westerbacka J, et al. Comparison of lipid and fatty acid composition of the liver, subcutaneous and intra-abdominal adipose tissue, and serum. Obesity (Silver Spring) 2009;18:937–944. [PubMed] One of the many articles citing low PUFAs in blood and tissues in humans with diabetes, obesity or metabolic syndrome.
38. Fernandez-Real JM, Broch M, Vendrell J, Ricart W Insulin resistance, inflammation, and serum fatty acid composition. Diabetes Care. 2003;26:1362–1368. [PubMed] One of the many articles citing low PUFAs in blood and tissues in humans with diabetes, obesity or metabolic syndrome.
39. Stoffel W, Holz B, Jenke B, et al. Delta-6 desaturase (FADS2) deficiency unveils the role of omega-3 and omega-6 polyunsaturated fatty acids. EMBO J. 2008;27:2281–2292. [PubMed] The first report on the consequences of global ablation of FADS2 on mouse physiology.
40. Stroud CK, Nara TY, Roqueta-Rivera M, et al. Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration. J Lipid Res. 2009;50:1870–1880. [PubMed] A second report on the consequences of global ablation of FADS2 on mouse physiology.
41. Nakamura MT, Nara TY. Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases. Annu Rev Nutr. 2004;24:345–376. [PubMed]
42. Hall D, Poussin C, Velagapudi VR, et al. Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced proinflammatory state. J Biol Chem. 2010;285:31011–31023. [PubMed] These investigators reported that resistance of A/J mice to diet-induced fatty liver is linked to elevated expression of enzymes involved in fatty acid oxidation and PUFA synthesis.
43. Moon YA, Hammer RE, Horton JD. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res. 2008;50:412–423. [PubMed]
44. Wang Y, Torres-Gonzalez M, Tripathy S, et al. Elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition. J Lipid Res. 2008;49:1538–1552. [PubMed]
45. Biddinger SB, Almind K, Miyazaki M, et al. 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. Wang Y, Inoue H, Ravnskjaer K, et al. Targeted disruption of the CREB coactivator CRTC2 increases insulin sensitivity. Proc Natl Acad Sci U S A. 2010;107:3087–3092. [PubMed]
47. Samuel VT, Beddow SA, Iwasaki T, et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with type 2 diabetes. Proc Natl Acad Sci U S A. 2009;106:12121–12126. [PubMed] An evidence that cytosolic phosphoenolpyruvate carboxykinase (Pck1) is not the sole determinant of the pace of gluconeogenesis in human and mice.
48. Burgess SC, He T, Yan Z, et al. Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metab. 2007;5:313–320. [PubMed] An evidence that cytosolic phosphoenolpyruvate carboxykinase (Pck1) is not the sole determinant of the pace of gluconeogenesis in human and mice.
49. Yang J, Kong X, Martins-Santos ME, et al. Activation of SIRT1 by resveratrol represses transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) by deacetylating hepatic nuclear factor 4alpha. J Biol Chem. 2009;284:27042–27053. [PubMed] This report is one of several documenting the role of SIRT1 in the control of Pck1 expression.
50. Rhee J, Inoue Y, Yoon JC, et al. Regulation of hepatic fasting response by PPARγ coactivator-1α (PGC-1α): requirement for hepatocyte nuclear factor 4α in gluconeogenesis. Proc Natl Acad Sci U S A. 2003;100:4012–4017. [PubMed]
51. Zhang W, Patil S, Chauhan B, et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006;281:10105–10117. [PubMed]
52. Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeo-genesis through FOXO1–PGC-1α interaction. Nature. 2003;423:550–555. [PubMed]
53. Matsumoto M, Pocai A, Rossetti L, et al. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 2007;6:208–216. [PubMed]
54. Qiang L, Accili D Uncoupling of acetylation from phosphorylation regulates FOXO1 function independent of its sub-cellular localization. J Biol Chem. 2010;285:27396–27401. [PubMed] The group has used mutation analysis to assess the role of FoxO1 phosphorylation and acetylation in intracellular trafficking of FoxO1 and its role in glucose metabolism.
55. Aoki M, Jiang H, Vogt PK. Proteasomal degradation of FoxO1 transcriptional regulator in cells transformed by P3K and Akt oncoproteins. Proc Natl Acad Sci U S A. 2004;101:13613–13617. [PubMed]
56. Guo S, Rena G, Cichy S, et al. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999;274:17184–17192. [PubMed]
57. Yan L, Lavin VA, Moser LR, et al. PP2A regulates the pro-apoptotic activity of FOXO1. J Biol Chem. 2008;283:7411–7420. [PubMed]
58. Wu Z, Jiao P, Huang X, et al. MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. J Clin Invest. 2010;120:3901–3911. [PubMed] This is a recent paper identifying MAPK phosphatase-3 as a key regulator of FoxO1 phosphorylation status and gluconeogenesis. At least two phosphatases control FoxO1 phosphorylation status, PP2A [57] and MKP-3.
59. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature. 2005;434:113–118. [PubMed]