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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2707.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hepatic PGC-1β Overexpression Induces Combined Hyperlipidemia and Modulates the Response to PPAR Activation

Christopher J. Lelliott; Anna Ljungberg; Andrea Ahnmark; Lena William-Olsson; Kim Ekroos; Anders Elmgren; Gunnel Arnerup; Carol C. Shoulders; Jan Oscarsson; Daniel Lindén

From AstraZeneca R&D (C.J.L., A.L., A.A., L.W.-O., K.E., A.E., J.O., D.L.), Mölndal, Sweden; the Wallenberg Laboratory for Cardiovascular Research (A.L., K.E., J.O., D.L.) and the Department of Physiology/Endocrinology (A.L., J.O.), The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden; VTT Technical Research Centre of Finland (K.E.), Espoo, Finland; Safety Assessment Sweden, AstraZeneca R&D (G.A.), Södertälje, Sweden; and MRC Clinical Sciences Centre (C.C.S.), Imperial Collage London, London, UK.

Correspondence to Daniel Lindén, AstraZeneca R&D, Department of Integrative Pharmacology (HE119), SE-431 83 Mölndal, Sweden. E-mail daniel.linden{at}astrazeneca.com

	Abstract

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Objective— Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor coactivator (PGC)-1β, and that in vitro both PGC-1β and PGC –1 increase PPAR-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPAR agonist Wy14,643 (Wy).

Methods and Results— C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1 or PGC-1β. On chow, hepatic PGC-1β overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPAR and hepatic lipase mRNA levels were reduced. PGC-1β overexpression blunted Wy-mediated changes in expression levels of PPAR and downstream genes. Furthermore, PGC-1β did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1β and PGC-1 overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1β overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC mRNA and plasma triglyceride levels.

Conclusions— Hepatic PGC-1β overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1β overexpression reduced the potentially beneficial effects of PPAR activation on gene expression. Thus, inhibition of hepatic PGC-1β may provide a therapy for treating combined hyperlipidemia.

The effects of increased hepatic expression of PGC-1 or PGC-1β on PPAR activation, gene expression, and lipid metabolism were investigated. PGC-1β overexpression induced a combined hyperlipidemia and blunted the effects of PPAR activation on gene expression. Thus, inhibition of hepatic PGC-1β may ameliorate combined hyperlipidemia and improve the effects of PPAR activators.

Key Words: DGAT • apolipoprotein B • adenovirus • hepatic lipase • hypertriglyceridemia

	Introduction

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The liver is a major determinant of the whole body metabolism of fatty acids and neutral lipids as well as circulating levels of atherogenic apolipoprotein (apo)B-containing lipoproteins.¹ By analogy, defective handling of fatty acids by the liver may contribute to the etiologies of Familial Combined Hyperlipidemia and the Metabolic Syndrome (MS) of Insulin Resistance, common conditions associated with marked increases in the secretion of neutral lipids in VLDL particles.^2–4 However, how this might relate to perturbed hepatic gene expression differences in such patients has not been explored.

Clinical studies have established that agonists for the peroxisome proliferator-activated receptor (PPAR), such as fibrates, improve atherogenic lipoprotein profiles and reduce the risk of coronary heart disease in certain patients with combined hyperlipidemia in the MS.^5,6 In the liver, PPAR activation regulates lipid metabolism pathways through transcriptional control of fatty acid uptake and oxidation, and the secretion of VLDL.^7–9

The inducible PPAR coactivators PGC-1 and PGC-1β induce common sets of genes, including nuclear-encoded subunits of the mitochondrial electron transport chain (ETC), plus distinct groups of genes involved in glucose and lipid metabolism.^10–16 Current data indicate that PGC-1 is a key regulator of the gluconeogenic response of the liver to fasting,^17–19 whereas PGC-1β coordinates the handling of acute lipid loads.²⁰ Thus, Lin et al have shown that short-term feeding of mice with a high-saturated fat diet (HFD) increases hepatic expression of PGC-1β. Furthermore, hepatic PGC-1β overexpression in rats fed HFD induced a sterol regulatory element binding protein (SREBP)-mediated lipogenic response associated with increased serum triglycerides and VLDL-cholesterol levels and reduced liver triglyceride content.²⁰

Although cell transfection studies, involving 3T3-L1 pre-adipocytes and SV40 T-antigen immortalized mouse hepatoma cells, have indicated that both PGC-1 and β coactivate PPAR in vitro,^16,21 the importance of such an activity for lipid homeostasis in the intact animal is unknown.

Here we report the effects in mice of hepatic PGC-1 and β overexpression on plasma and liver lipid levels, liver triglyceride secretion, and PPAR- and SREBP-1–mediated gene expression under both chow and HFD dietary regimens.

	Materials and Methods

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C57BL/6 mice were fed standard chow diet containing (energy %) 12% fat, 62% carbohydrates, and 26% protein, with a total energy content of 12.6 kJ/g or a HFD (D12331, Research Diets) used by Lin et al,²⁰ containing 58% fat, 26% carbohydrates, and 16% protein, with a total energy content of 23.3 kJ/g. Weight-matched mice were transduced with recombinant adenoviruses expressing either PGC-1, PGC-1β, or the control ZsGreen via tail vein injections alone or in combination with administration of the selective PPAR agonist Wy 14, 643 (Wy, 30 µmol/kg/d in 0.5% (wt/vol) methyl cellulose). Experimental procedures were approved by the Ethics Review Committee on Animal Experiments (Gothenburg region). Please see the online data supplement for further experimental details, available online at http://atvb.ahajournals.org.

	Results

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Liver-Directed Overexpression of PGC-1β Results in Combined Hyperlipidemia
An initial dose-response experiment using 0.5x10⁹, 1x10⁹, or 2x10⁹ infectious units (ifu) of recombinant adenoviruses encoding either PGC-1, PGC-1β, or the control gene ZsGreen showed that PGC-1β (40-fold maximum increase), but not PGC-1 (11-fold maximum increase), overexpression increased plasma levels of triglycerides, cholesterol, and apoB (supplemental Figure I, available online at http://atvb.ahajournals.org). To avoid differences in ALT levels between groups and restrict expression of the gene products to the liver,²² subsequent experiments were performed with 1.2x10⁹ ifu of recombinant adenoviruses. Dosing at 1.2x10⁹ ifu increased PGC-1 and PGC-1β mRNA levels by 4- and 14-fold, respectively (supplemental Table I, available online at http://atvb.ahajournals.org), and confirmed that Ad-PGC-1β specifically induces high plasma cholesterol and triglyceride levels. No differences were observed in liver triglyceride (supplemental Table I and supplemental Figure IIA) or diglyceride content (data not shown). However, Ad-PGC-1β increased liver cholesterol ester, phosphatidylcholine, and phosphatidylethanolamine levels (supplemental Figure IIB through IID).

We examined the impact of PGC-1β overexpression on the hepatic triglyceride secretion in vivo using intravenous administration of Triton WR-1339. The experiment was performed with 0.5x10⁹ ifu of Ad-PGC-1β. Plasma triglyceride levels were raised by 87% compared with the mice transduced with the control Ad-ZsGreen virus, whereas the triglyceride secretion rate was elevated by 44% (Figure 1). Thus, our data suggest that PGC-1β–induced combined hyperlipidemia stems, at least in part, from an increased secretion rate of triglyceride-rich VLDL from the liver.

View larger version (10K): [in this window] [in a new window]   Figure 1. Effects of hepatic PGC-1β overexpression on baseline plasma triglyceride (TG) levels (A) and in vivo TG secretion rate (B). Ad-PGC-1β or Ad-ZsGreen were injected via the tail vein (0.5x109 ifu) and after 5 days plasma TG levels were determined before injection (0 minutes=baseline TG) and at 30, 60, and 90 minutes after Triton WR-1339 injection. Values are means±SEM (n=6). *P<0.05; PGC-1β vs ZsGreen, Mann–Whitney U test.

PGC-1β Overexpression Blunts the Effect of Wy on PPAR-Target Gene Expression
In a separate experiment, we administered the PPAR agonist Wy to mice transduced with Ad-PGC-1, Ad-PGC-1β, or Ad-ZsGreen (1.2x10⁹ ifu) to investigate whether PGC-1 overexpression enhances the effects of PPAR activation as suggested from in vitro experiments.^16,21 Plasma ALT levels did not differ between the virus groups (supplemental Table II). Consistent with initial data, hepatic overexpression of PGC-1β increased plasma triglyceride, free fatty acid (FFA), cholesterol, and apoB levels, whereas the PGC-1 transgene did not (Figure 2A through 2D). Accordingly, PGC-1β, but not PGC-1, overexpression markedly increased the plasma levels of VLDL and IDL/LDL lipoproteins (Figure 2E). Wy administration modestly increased plasma cholesterol levels in ZsGreen and PGC-1–transduced mice but not in mice transduced with PGC-1β (Figure 2C). Wy increased mean liver weight irrespective of virus treatment (supplemental Table II) but neither PGC-1 overexpression nor Wy treatment influenced liver triglyceride content (Figure 2F). In short, Wy treatment did not ameliorate the lipid abnormalities of PGC-1β–induced hyperlipidemia.

View larger version (25K): [in this window] [in a new window]   Figure 2. Effects of combined hepatic PGC-1 or PGC-1β overexpression and Wy administration on plasma triglyceride (A), free fatty acids (FFA) (B), cholesterol (C), apolipoprotein (apo)B levels (D), cholesterol lipoprotein profile (E), and liver triglyceride content (F). Male C57BL/6 mice were given Wy (30 µmol/kg/d) for 7 days. Ad-PGC-1, Ad-PGC-1β, or Ad-ZsGreen were injected via the tail vein (1.2x109 ifu) after 2 days Wy administration. Values are means±SEM (n=6 to 7). *P<0.05; PGC-1 or PGC-1β vs ZsGreen, # P<0.05; Wy vs vehicle treatment in respective virus group, Kruskal–Wallis test followed by Mann–Whitney U test.

Hepatic overexpression of PGC-1β decreased PGC-1 transcript levels, and Wy reduced these further (Figure 3A). By contrast, hepatic PGC-1β mRNA was unaffected by high expression of PGC-1 and Wy administration (Figure 3B). Livers from mice transduced with Ad-PGC-1β had lower PPAR mRNA levels than livers from mice overexpressing PGC-1 or the ZsGreen transgene (Figure 3C). As expected, Wy upregulated PPAR responsive genes^7,9; PPAR itself, medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD), acyl-CoA oxidase-1, CYP4a10, and adipose differentiation-related protein mRNA levels in all groups of mice (Figure 3C through 3G). However, the upregulation was smaller in PGC-1β–transduced mice compared with ZsGreen transduced mice and intermediate in PGC-1 mice (Figure 3C through 3G). Wy also lowered apoCIII mRNA in both Ad-ZsGreen and Ad-PGC-1 mice but not in PGC-1β–transduced mice (Figure 3H). Thus, these data indicate that hepatic PGC-1β overexpression in vivo blunts the normal gene expression response to PPAR activation.

View larger version (20K): [in this window] [in a new window]   Figure 3. Effects of combined hepatic PGC-1 or PGC-1β overexpression and Wy administration on mRNA levels in liver: PGC-1 (A), PGC-1β (B), PPAR (C), MCAD (D), ACO1 (E), Cyp4a10 (F), ADRP (G), and ApoC-III (H) mRNA expression. Mice were treated as described in Figure 2. Values are means±SEM (n=6 to 7). *P<0.05; PGC-1 or PGC-1β vs ZsGreen, #P<0.05; Wy vs vehicle treatment in respective virus group, P<0.05; Wy ZsGreen vs Wy PGC-1β, Kruskal–Wallis test followed by Mann–Whitney U test.

We also determined the effect of PGC-1β overexpression on PPAR-mediated fatty acid oxidation in primary mouse hepatocytes (supplemental Figure III). Wy incubation increased the fatty acid oxidation in ZsGreen overexpressing cells by 420%. PGC-1β overexpression increased the fatty acid oxidation by 230%. However, Wy treatment of PGC-1β overexpressing hepatocytes only increased the fatty acid oxidation by 72% (supplemental Figure III). Thus, PGC-1β overexpression failed to potentiate the Wy-induced rise in fatty acid oxidation.

PGC-1β Overexpression Specifically Induces Hepatic DGAT1 Expression
In contrast to observations in HFD-fed rats,²⁰ PGC-1β overexpression did not increase hepatic mRNA levels of SREBP-1c or the SREBP-target genes, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (Figure 4A). Acyl CoA: diacylglycerol acyltransferase (DGAT) 1 mRNA was substantially increased in livers from Ad-PGC-1β animals (Figure 4A). Transcript levels of liver X receptor (LXR), and other measured genes active in triglyceride biosynthesis (eg, mitochondrial glycerol-3-phosphate acyltransferase [mtGPAT], DGAT2) were comparable to control animals (Figure 4A). Likewise, transcripts promoting lipogenesis (acetyl-CoA carboxylase , ACC), fatty acid desaturation (stearoyl-CoA desaturase-1, SCD-1), and lipid transfer (microsomal triglyceride transfer protein, MTTP) were unaltered by PGC-1β overexpression (Figure 4A). Consistent with gene expression data (Figure 4A), protein levels for DGAT1, but not MTTP, were increased (Figure 4B).

View larger version (27K): [in this window] [in a new window]   Figure 4. Effects of hepatic PGC-1 or PGC-1β overexpression on lipogenic and triglyceride gene expression profiles (A), DGAT1, MTTP and PDI protein expression (B), transcript levels of lipid uptake genes (C), fatty acid oxidation and electron transport chain genes (D), and electron microscopy of livers (E). Mice were treated with viruses as described in Figure 2. Values are means±SEM (n=6). *P<0.05; PGC-1 or PGC-1β vs ZsGreen, Kruskal–Wallis test followed by Mann–Whitney U test. Representative electron microscopy pictures are shown (m indicates mitochondria).

Hepatic overexpression of PGC-1β, but not PGC-1, was associated with decreased hepatic lipase levels, whereas both coactivators were associated with increased transcript levels for the fatty acid uptake gene, translocase (FAT)/CD36 (Figure 4C). Likewise, both PGC-1 and β overexpression increased hepatic transcript levels for the fatty acid oxidation gene, MCAD (Figure 4D). By contrast, PGC-1β overexpression caused a more pronounced increase in ETC transcripts: cytochrome C (CytC), cytochrome oxidase (Cox)5b, and Cox4 (Figure 4D). Consistent with increased mitochondrial biogenesis, electron microscopy analyses of representative livers from Ad-PGC-1β mice revealed increased numbers of mitochondria relative to control livers from Ad-ZsGreen mice (Figure 4E).

Thus, collectively our data indicate that PGC-1β overexpression in chow-fed mice mediates specific changes in hepatic gene expression and that these translate into increased CD36-mediated uptake of fatty acids (Figure 4C), increased fatty acid oxidation (Figure 4D and supplemental Figure III), increased incorporation of fatty acids into neutral lipids (Figure 2A through 2C, Figure 4A, supplemental Figure II), mitochondrial biogenesis (Figure 4D and 4E), and increased hepatic secretion of triglyceride-rich lipoproteins (Figure 1).

Effects of PGC-1β Overexpression in Fat-Fed Mice
The observation that PGC-1β overexpression in chow-fed mice had no effect on hepatic mRNA levels for SREBP-1c, or a range of downstream targets of SREBP-1c, contrasts with data from HFD-fed rats.²⁰ We therefore fed mice HFD and examined hepatic gene expression and plasma and liver lipid profiles (Table). HFD increased hepatic SREBP-1c, LXR, PGC-1β, and PPAR mRNA levels by 133%, 20%, 49%, and 81%, respectively. Increased transcript levels were also observed for the downstream targets of SREBP-1c: ACC, FAS, SCD-1, mtGPAT, and DGAT2 (Table).

View this table: [in this window] [in a new window]   Table. Effects of High-Fat Diet and Hepatic PGC-1β Overexpression on Liver Gene Expression and Plasma and Liver Lipid Levels

On HFD, PGC-1β overexpression decreased PGC-1 and PPAR expression (Table) as previously observed in chow fed mice (Figure 3A and 3C). Furthermore, PGC-1β overexpression decreased SREBP-1c mRNA levels whereas ACC and FAS mRNA were increased by 39% and 73%, respectively. SCD-1, mtGPAT, and LXR expression levels did not change significantly, whereas DGAT1 was markedly upregulated (249%) by PGC-1β overexpression (Table). PGC-1β overexpression increased plasma triglyceride levels but did not change plasma cholesterol levels or liver triglyceride content (Table). Thus, HFD increases PGC-1β, SREBP-1c, and downstream target gene expression levels. Furthermore, the hypertriglyceridemia induced by PGC-1β overexpression correlates with DGAT1 upregulation while no consistent changes in SREBP-1c or SREBP-1c regulated genes were observed.

	Discussion

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This study demonstrates that liver-specific overexpression of PGC-1β, but not PGC-1, leads to hypertriglyceridemia, hypercholesterolemia, and abnormal VLDL, IDL/LDL levels in mice fed chow diet consistent with data reported in fat-fed rats.²⁰ In the current study, the observation of elevated plasma apoB levels clearly shows development of an atherogenic lipoprotein phenotype²³ that is associated with increased triglyceride secretion rate from the liver and elevated plasma levels of FFA. PGC-1β overexpression increased hepatic levels of DGAT-1 and CD36 mRNA whereas hepatic lipase was decreased. However, upregulation of SREBP-1c–mediated lipogenic gene expression was not obligatory for the PGC-1β–induced hyperlipidemia. The study also reveals that the PPAR agonist, Wy, did not ameliorate PGC-1β–induced combined hyperlipidemia. In contrast, PGC-1β expression blunted the normal PPAR-mediated regulation of downstream target genes and PGC-1β did not potentiate Wy-stimulated fatty acid oxidation. These findings suggest that the effectiveness of PPAR agonists as a lipid lowering therapy may be reduced in hyperlipidemic patients consuming a HFD and that increased expression of hepatic CD36 and DGAT1, plus reduced levels of hepatic lipase, may be causally linked to the development of PGC-1β–induced combined hyperlipidemia.

Several lines of evidence support the proposition that the combination of increased hepatic CD36 and DGAT1 expression and reduced hepatic lipase are causally linked to PGC-1β–induced combined hyperlipidemia. Firstly, CD36 promotes cellular uptake of FFA.²⁴ Secondly, Yamazaki et al²⁵ have shown that overexpression of DGAT1, but not DGAT2, in mouse liver raises triglyceride secretion and plasma VLDL. Thirdly, overexpression of hepatic lipase in both rabbits and mice leads to low plasma cholesterol and apoB-containing lipoprotein levels,^26,27 whereas deficiency of hepatic lipase in mice²⁸ and humans²⁹ causes combined hyperlipidemia.

In accordance with Lin et al,²⁰ we found that HFD induced hepatic PGC-1β, SREBP-1c, and SREBP-1c downstream target genes. Additionally, LXR mRNA was modestly increased. However, in contrast to fat-fed rats,²⁰ the combined hyperlipidemia observed in our model of liver-specific PGC-1β overexpression in chow-fed mice was not associated with decreased liver triglyceride content. Instead, liver content of cholesterol esters and phospholipids increased, which might help to explain the increased liver size. The differences in liver triglyceride content between our study and the study by Lin et al²⁰ could be species dependent or attributable to the fact that we did not find that elevated hepatic PGC-1β expression increased SREBP-1c. However, SREBP-1c has been shown in vivo to promote hepatic lipid accumulation and reduce plasma triglyceride levels.³⁰ Although PGC-1β overexpression moderately increased both FAS and ACC in HFD-fed mice, the gene expression level of SREBP-1c was decreased and both SCD-1 and mtGPAT levels were unchanged. Thus, there was no consistent change in SREBP-1c or SREBP-1c regulated genes by PGC-1β overexpression in mice on HFD. Therefore, the hypertriglyceridemia that occurred after PGC-1β overexpression in HFD-fed mice relates better to increased DGAT1 expression, as also observed on chow diet.

It has been reported that hepatic PGC-1β overexpression mediates the metabolic effects of the forkhead transcription factor A2 (Foxa2) in ob/ob mice.³¹ Specifically, concomitant overexpression of Foxa2 and PGC-1β markedly increased VLDL-triglyceride secretion, whereas PGC-1β alone had minor effects in this model.³¹ This difference from our studies likely arises because hyperinsulinemia and insulin-resistance inactivate Foxa2,³² and thus would be predicted to reduce Foxa2 activity in ob/ob mice³¹ but not in C57BL/6 mice. Nonetheless, the observation that combined overexpression of a constitutively active Foxa2 and PGC-1β in ob/ob mice increased DGAT2 and MTTP expression³¹ suggests that a different, albeit overlapping, mechanism contributes to the hyperlipidemia observed in this model.

The observation that hepatic PGC-1 mRNA was reduced in the setting of increased expression of PGC-1β is consistent with recent data showing that PGC-1β–deficient mice have higher levels of PGC-1 expression.^33–35 Here, we show the overexpression of both PGC-1β and PGC-1 induced modest increases in hepatic transcripts encoding gene products active in fatty acid oxidation and that both coactivators were associated with increased transcription of genes encoding subunits of the mitochondrial ETC. Thus, in contrast to PGC-1β–deficient mice which have reduced ETC gene expression and mitochondrial number,^33–35 hepatic overexpression of PGC-1β had the opposite effect. However, this increased fatty acid oxidative capacity was insufficient to prevent or reverse the development of a combined hyperlipidemia in these animals.

In marked contrast to the observations in vitro,^16,21 neither PGC-1 nor PGC-1β potentiated the effects of the PPAR agonist, Wy, on PPAR target gene expression or fatty acid oxidation. Rather, PGC-1β overexpression blunted the effects of PPAR activation on gene expression and failed to ameliorate the PGC-1β–induced combined hyperlipidemia. Additionally, PGC-1 mRNA levels were markedly reduced. Thus, normal levels of PGC-1 may be critical for maintaining the PPAR response in vivo. Alternatively, PGC-1β preferentially coactivates another receptor in the liver³⁶ or induces an unknown factor in vivo that inhibits the effects of PPAR activation. The marked contrast between in vitro^16,21 and our in vivo data highlights the importance of studying interactions between nuclear receptors and coactivators in vivo.

In summary, hepatic overexpression of PGC-1β, which is upregulated by dietary fats in mice and rats, increases in vivo liver triglyceride secretion, generating a combined hyperlipidemia phenotype and elevated plasma levels of FFA. The effects of PPAR activation on gene expression are not potentiated, but rather blunted by PGC-1β overexpression in vivo. These results suggest that liver-specific inhibition of PGC-1β expression may provide a therapeutic approach for treating combined hyperlipidemia, and that defects in pathways regulated by PGC-1β in the liver may contribute to the highly atherogenic lipoprotein profiles of Familial Combined Hyperlipidemia and the MS.

	Acknowledgments

 
We are grateful to Marie Johansson, Monica Fredberg, Anette Bergström, and Anders Elmgren’s group for expert technical assistance.

Sources of Funding

We acknowledge the support from the British Heart Foundation and the Medical Research Council (CCS).

Disclosures

C.J.L., A.L., A.A., L.W.-O., K.E., A.E., G.A., J.O., and D.L. are employed by AstraZeneca and have stocks in AstraZeneca.

	Footnotes

 
C.J.L. and A.L. contributed equally to this study.

Original received October 6, 2006; final version accepted September 21, 2007.

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