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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1642-1646, July 2005

Biochemical and Molecular Actions of Nutrients

Fructose Selectively Modulates c-jun N-Terminal Kinase Activity and Insulin Signaling in Rat Primary Hepatocytes1,2

Yuren Wei, Dong Wang and Michael J. Pagliassotti3

Colorado State University, Department of Food Science and Human Nutrition, Fort Collins, CO 80523

3To whom correspondence should be addressed. E-mail: pagliasm{at}cahs.colostate.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Fructose is a unique nutrient, due in part to its selective metabolism in the liver. Diets enriched in fructose or sucrose induce a hepatic stress response characterized by activation of c-jun N-terminal kinase. The aim of this study was to examine the regulation of c-jun N-terminal kinase by fructose in rat primary hepatocytes. Fructose was provided to rat primary hepatocytes using a fructose regenerating system, consisting of inulin and inulinase. This system provides a more physiologic delivery of fructose and avoids large disturbances in hepatocyte ATP concentrations. Fructose delivery increased c-jun N-terminal kinase activity and serine 307 phosphorylation of insulin receptor substrate-1 and reduced tyrosine phosphorylation of insulin receptor substrate-1. Activation of c-jun N-terminal kinase was maximal at a fructose concentration of 0.6 mmol/L. Fructose delivery did not increase the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal regulated kinase, c-jun, or activating transcription factor-2, the latter 2 downstream nuclear targets of c-jun N-terminal kinase. However, fructose delivery increased the phosphorylation of mitogen-activated protein kinase kinase-7 (MKK7), an upstream activator of c-jun N-terminal kinase, and the association of c-jun N-terminal kinase with c-jun N-terminal kinase-interacting protein-1, a scaffold protein that can sequester protein signaling complexes in the cytosol. These data suggest that fructose may selectively activate c-jun N-terminal kinase via regulation of MKK7 and scaffold proteins.

KEY WORDS: • rats • liver • fructose • stress

The prevalence of obesity, and therefore insulin resistance and the metabolic syndrome, is increasing, and many causes have been proposed to account for this epidemic, including diet composition (1–4). One scenario that has been used to explain the role of diet composition involves increased access to diets enriched in fat or foods and beverages containing added simple sugars (i.e., sucrose, high-fructose corn syrup), positive energy balance, and weight/fat gain (1–3). Indeed, increased consumption of added simple sugars in the United States, in particular high-fructose corn syrup, appears to mirror the increase in obesity and type 2 diabetes (2,3,5).

Dietary nutrients can also directly modulate insulin action. In rats, diets enriched in sucrose or fructose produce hepatic insulin resistance before adipose tissue and skeletal muscle, and independently of changes in body composition (6). Sucrose-induced hepatic insulin resistance occurred concomitantly with elevated hepatic c-jun N-terminal kinase (JNK)4 activity, and normalization of JNK activity in isolated hepatocytes improved insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and insulin suppression of glucose release (7). The ingestion of a single, sucrose-enriched meal or elevation of portal vein fructose concentrations to ~1 mmol/L via fructose infusion in rats in vivo also increased hepatic JNK activity and phosphorylation of IRS-1 on serine 307, a downstream target of JNK that can negatively modulate insulin signaling (7–9). Importantly, fructose infusions in humans can also induce hepatic insulin resistance (10). The present study was designed to examine the regulation of JNK by fructose in rat primary hepatocytes using a unique fructose delivery system (11).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animals. Male Wistar Crl:(WI)BR rats (Charles River) weighing ~150 g upon arrival had free access to a high-starch diet and water for 1 wk. The diet was formulated by Research Diets, with a composition consisting of casein, 200 g/kg; DL-methionine, 3 g/kg; cornstarch, 500 g/kg; maltodextrin 10, 150 g/kg; cellulose, 50 g/kg; corn oil, 50 g/kg; salt mix, 35 g/kg; vitamin mix, 10 mg/kg; and choline bitartrate, 2 mg/kg (6,12). Rats were housed individually in a temperature- and humidity-controlled environment with a 12-h light:dark cycle. Surgical procedures and experiments were performed after 1 wk of acclimatization. All procedures were reviewed and approved by the Colorado State University institutional animal care committee.

    Hepatocyte isolation and cultures. Hepatocytes were isolated from rats by collagenase perfusion (13). Viability, based on trypan blue exclusion, was >90%. Cells were first incubated with RPMI 1640 containing 11 mmol/L glucose, 100 nmol/L dexamethasone, and 100 nmol/L insulin on collagen-coated plates containing 5% fetal bovine serum for 4 h. After attachment, the medium was changed to one containing RPMI, 8 mmol/L glucose, 100 nmol/L dexamethasone, and 10 nmol/L insulin. The following morning experimental treatments were performed using RPMI (14). Each experiment was performed in triplicate.

    Experimental model. To perform these studies, a fructose regenerating system developed by Phillips et al. (11) was employed. In brief, inulinase and inulin were used to generate fructose at a rate designed to match fructose utilization. This delivery system minimizes disturbances in ATP and redox status that result from exposing cells to high concentrations of sugars or to nutrient limitation, which can easily occur with rapidly metabolized sugars (e.g., fructose) (15,16). Rat primary hepatocytes (n = 10) were incubated in a medium consisting of 8 mmol/L glucose, 1 mmol/L fructose, and 0.12% (wt:v) inulin (F1). Fructose (Fig. 1A) and ATP (Fig. 1B) were reduced, reaching nadirs by ~90 min. In the other 4 treatments, different concentrations of inulinase were added to the medium. A concentration of inulinase between 20 and 40 mU was sufficient to generate fructose at a rate that approximated fructose utilization over a 5-h period. An inulinase concentration of 28 ± 2 mU resulted in an effective "fructose clamp" at ~1 mmol/L over a 5-h period (horizontal line on the graph of fructose concentration would indicate a perfect match of fructose delivery to removal). Maintenance of fructose concentrations preserved ATP levels and changes in ATP that occurred with 20–40 mU of inulinase were similar to those observed when the liver was exposed to potential postprandial concentrations (~1 mmol/L) of fructose in vivo (17,18).



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  		FIGURE 1 Fructose concentration in the medium (A) and ATP concentrations in hepatocytes (B) after incubation of primary hepatocytes in the presence of 8 mmol/L glucose, 1 mmol/L fructose, and 0.12% (wt:v) inulin in the absence (F1) or presence of different concentrations of inulinase (I). Values are means ± SEM, n = 10/incubation condition.

 
Studies were performed using the following incubation conditions: Control incubations (G) contained 8 mmol/L glucose and 0.12% (wt:v) inulin; experimental incubations (GF) contained 8 mmol/L glucose, 1 mmol/L fructose, 0.12% (wt:v) inulin, and 28 mU inulinase. When present, insulin was used at a concentration of 1 nmol/L and SP600125, a specific inhibitor of JNK (Calbiochem), was used at a concentration of 25 µmol/L.

    Cell processing. After the incubations, cells were washed with PBS and scraped from culture dishes using a buffer containing 20 mmol/L (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]), pH 7.4; 1% Triton; 10% glycerol; 2 mmol/L EGTA; 2 mmol/L dithiothreitol; 10 µmol/L leupeptin; 5 µmol/L pepstatin; 10 mg/L aprotinin; 50 mmol/L ß-glycerophosphate; 3 mmol/L benzamidine; 1 mmol/L 4-(2-amnoethyl)benzenesulfonylfluoride; and 1 mmol/L sodium vanadate. Cell suspensions were homogenized by 20 passages through a ball bearing homogenizer and centrifuged at 20,000 x g for 30 min at 4°C. Supernatants were analyzed for total protein (Lowry method) and used for immunoprecipitation and/or immunoblot analysis.

    Immunoprecipitation and Western blot analysis. For immunoprecipitations, equivalent amounts of protein were incubated with antibodies against IRS-1 (Upstate Biotechnology), IRS-2 (Upstate Biotechnology), JNK (Cell Signaling) or JNK-interacting protein 1 (JIP1, Santa Cruz Biotechnology) followed by incubation with Protein A- or G-agarose (Upstate Biotechnology). Immunoprecipitated proteins were resolved by SDS-PAGE, electrotransferred to Hybond-P membranes (Amersham Pharmacia Biotech) and membranes incubated with antibodies against phosphotyrosine (pY; BD Transduction Laboratories), IRS-1, JNK1/2 (Cell Signaling), or JIP1 (Santa Cruz Biotechnology). Detection was performed using enhanced chemiluminescence reagents (Amersham Pharmacia Biotech), and band intensity was analyzed by optical density (UVP Bioimaging system).

In some cases, protein amounts were determined without immunoprecipitation. Equivalent amounts of protein were subjected to SDS-PAGE, as described above, and membranes incubated with antibodies against phospho-serine 307 of IRS-1 (IRS-1307; Upstate Biotechnology), phospho-p42/p44 mitogen-activated protein (MAP) kinase (p-ERK1/2; Cell Signaling), phospho-p38 MAP kinase (p-p38; Cell Signaling), phospho-c-Jun (Cell Signaling), or phospho-activating transcription factor-2 (p-ATF-2, Cell Signaling). Membranes were processed as described above.

    c-Jun terminal kinase (JNK) activity. Cell lysates were incubated with an N-terminal c-Jun (1–89) fusion protein bound to glutathione sepharose beads (Cell Signaling). The kinase reaction was initiated by the addition of 100 µmol/L ATP. Western blot analysis was used to detect the level of c-Jun phosphorylation using an antibody specific for serine 63 (Cell Signaling).

    Biochemical analysis. Fructose and glucose concentrations were determined using standard enzymatic procedures (7).

    Data analysis and statistics. Data are presented as means ± SEM. Two-way repeated-measures ANOVA was used to analyze the effects of fructose and time. Post-hoc analyses included linear contrasts and Student-Newman-Keul’s test. An {alpha}-level of P < 0.05 was used for statistical significance.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Activation of JNK in response to fructose regeneration. Initial studies (n = 6) were performed to determine whether fructose regeneration activated JNK and increased phosphorylation of IRS-1307 in rat primary hepatocytes. Similar to our previous in vivo studies (7), JNK activity was increased by GF at 2 and 4 h (Fig. 2). Activation of JNK was not observed at fructose concentrations of ≤0.4 mmol/L and was maximal at concentrations of 0.6 mmol/L (Fig. 3, n = 6). GF also increased phosphorylation of IRS-1307 in the absence or presence of insulin and reduced tyrosine phosphorylation of IRS-1 and IRS-2 in the presence of insulin (Table 1). GF did not increase phosphorylation of p38 MAP kinase or ERK1/2 (Table 1). The effects of GF were not due to inulinase because incubation of hepatocytes with 8 mmol/L glucose and 28 mU inulinase had no effect on any of the above variables (data not shown). To rule out osmotic effects, 1 mmol/L mannitol was added to an incubation medium containing 8 mmol/L glucose and 0.12% inulin. This treatment also had no effect (data not shown). Addition of the selective JNK inhibitor (7,19), SP600125, did not inhibit fructose utilization (fructose clamp was maintained) but normalized both JNK activity and IRS-1307 phosphorylation, and improved tyrosine phosphorylation of IRS-1 after 4-h incubations in the presence of 1 nmol/L insulin (Fig. 4, n = 6).



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  		FIGURE 2 JNK activity in total cell lysates isolated from primary hepatocytes after incubations with 8 mmol/L glucose and 0.12% inulin (G) or 8 mmol/L glucose, 1 mmol/L fructose, 0.12% inulin and 28 mU inulinase (GF) in the absence (–) or presence (+) of 1 nmol/L insulin. Results are from densitometric analysis with G in the absence of insulin set to an arbitrary unit of 1. Values are means ± SEM, n = 6. Bars without a common letter differ, P < 0.05. Representative gel from 4 h time point provided at top.

 


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  		FIGURE 3 JNK activity in total cell lysates isolated from primary hepatocytes after incubations with 8 mmol/L glucose and 0.12% inulin (G) or 8 mmol/L glucose, 0.12% inulin, and varying concentrations of fructose and inulinase (GF). Results are from densitometric analysis with G set to an arbitrary unit of 1. Values are means ± SEM, n = 6. Bars without a common letter differ, P < 0.05.

 

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  		TABLE 1 Phosphorylation of IRS-1307, tyrosine phosphorylation (pY) of IRS-1 and IRS-2, phosphorylation of p38 MAP kinase (p-p38), and phosphorylation of extracellular signal-regulated kinase (p-ERK) in primary hepatocytes after incubations in the absence or presence of fructose regeneration1

 


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  		FIGURE 4 JNK activity, phosphorylation of serine 307 on IRS-1 (IRS1307), and tyrosine phosphorylation of IRS-1 (IRSpY) in total cell lysates isolated from primary hepatocytes after 4-h incubations with 8 mmol/L glucose and 0.12% inulin (G) or 8 mmol/L glucose, 1 mmol/L fructose, 0.12% inulin and 28 mU inulinase (GF) in the presence of 1 nmol/L insulin and the absence (–) or presence (+) of SP600125. Results are presented as arbitrary density units. Values are means ± SEM, n = 6. Bars without a common letter differ, P < 0.05.

 
    Selectivity of fructose activation of JNK. Activating transcription factor (ATF)-2 and c-jun are 2 nuclear targets of JNK (20). After a 4-h incubation (n = 6), GF did not increase phosphorylation of ATF-2 or c-jun (Fig. 5, n = 6). JIP1 is a scaffold protein that may function to retain protein signaling modules in the cytosol (21,22). Total cell lysates were immunoprecipitated with an antibody against JIP1 and immunoblotted with an antibody against JNK or immunoprecipitated with an antibody against JNK and immunoblotted with an antibody against JIP1. GF increased the association of JNK with JIP1 in the absence or presence of insulin (Fig. 5, n = 6).



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  		FIGURE 5 Phosphorylation of ATF-2, phosphorylation of cjun, and the association of JNK with JIP1 after 4-h incubations in the absence or presence of 1 nmol/L insulin. G contained 8 mmol/L glucose and 0.12% inulin and GF, 8 mmol/L glucose, 1 mmol/L fructose, 0.12% inulin, and 28 mU inulinase. IP, immunoprecipitation; IB, immunoblot. Results are from densitometric analysis with G– set to an arbitrary unit of 1. Values are means ± SEM, n = 6. Bars without a common letter differ, P < 0.05. Representative gel provided.

 
    Fructose increases phosphorylation of MKK7. JNK is activated by sequential protein phosphorylation through a MAP kinase (MAPK) module (20). Two MAPK kinases for JNK, MKK4 and MKK7, have been identified (23). Unlike MKK7, which appears to be specific to JNK, MKK4 can phosphorylate both JNK and p38 (23). GF increased phosphorylation of MKK7 but not MKK3, MKK4, or MKK6 (Fig. 6, n = 6).



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  		FIGURE 6 Phosphorylation of MKK3, MKK4, MKK6, and MKK7 after 4-h incubations in the absence or presence of 1 nmol/L insulin. G contained 8 mmol/L glucose and 0.12% inulin and GF, 8 mmol/L glucose, 1 mmol/L fructose, 0.12% inulin and 28 mU inulinase. Results are from densitometric analysis with G– set to an arbitrary unit of 1. Values are means ± SEM, n = 6. Bars without a common letter differ, P < 0.05. Representative gel provided.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
The present study, similar to our previous in vivo studies (7), demonstrates that fructose activates JNK activity and modifies the phosphorylation state of both IRS-1 and IRS-2 in rat primary hepatocytes. New data demonstrate that fructose delivery 1) increased the phosphorylation of MKK7, 2) did not increase phosphorylation of the JNK nuclear targets, cjun and ATF2, and 3) increased the association of JNK with JIP1.

Fructose delivery generates a unique and selective signal within the hepatocyte that culminates in the activation of JNK and modulation of insulin signaling (7,24,25). It was hypothesized that hepatic stress in response to elevated fructose concentrations results from the burden of fructose metabolism (7,18,24). However, the intrahepatic signal(s) that mediate fructose-induced activation of stress signaling and modulation of insulin action have not been identified. Future studies will use this novel fructose regenerating system to identify the cellular intermediates and signals responsible for fructose-induced changes in protein signaling.

The JNK family of kinases are members of the MAPK family and can be activated by a diverse set of stimuli (23,26). JNK is activated by sequential phosphorylation through a MAPK module (MAPKKK -> MAPKK -> MAPK) (20,27). Two MAPKK that regulate JNK, MKK4 and MKK7 have been identified (28). Although both MKK4 and 7 appear to be required for full activation of JNK, differential phosphorylation of JNK by MKK4 or 7 may provide a molecular basis for the regulation of JNK by various stimuli (27). In the present study, we show that the signal generated by fructose delivery in the hepatocyte increases the phosphorylation of MKK7 but not MKK4. These data suggest, but do not prove that the MAPK signaling module that responds to fructose delivery includes MKK7 and JNK. Scaffold proteins, such as JIP and JNK-associated leucine zipper protein, facilitate assembly of JNK signaling modules (29). In particular, JIP proteins may function to retain protein signaling modules in the cytosol (30,31). In the present study, fructose delivery increased JNK activity and modulation of the phosphorylation state of IRS proteins, but did not lead to increased phosphorylation of nuclear targets of JNK (i.e., cjun and ATF2). This selectivity of JNK action in response to fructose delivery may be mediated by the observed increase in the association of JNK with JIP1. Thus, the selective activation of JNK and downstream targeting to IRS proteins in response to fructose delivery appears to involve a protein signaling module that minimally includes MKK7, JNK, and JIP1. Future studies will examine the direct role of these proteins in fructose-induced insulin resistance.

The cell system used in the present study, although offering several advantages, does not mimic the dynamic nature of in vivo dietary nutrient delivery. With this in mind, this cellular model system was employed only after studies that demonstrated that diets enriched in sucrose or fructose, or fructose infusion in rats in vivo, increased hepatic JNK activity and phosphorylation of serine 307 on IRS-1 (7,24). It is likely that the magnitude of hepatic stress induced by fructose will ultimately depend on the concentration presented to the liver, the duration of exposure to increased fructose delivery, as well as multiple biologic and genetic factors (14,32–34). It is also presently uncertain how JNK interactions with IRS-2 modify tyrosine phosphorylation of this protein (8).

In summary, increased fructose delivery in primary hepatocytes increased JNK activity and selectively modified the phosphorylation state of IRS proteins. This selectivity may involve the upstream MAPK kinase, MKK7, and the scaffold protein JIP1. It is hypothesized that increased consumption of high-fructose corn syrup and refined carbohydrates can place an inordinate burden for metabolism on the liver and can, under some circumstances, provoke adaptations that involve specific stress signaling pathways.


   FOOTNOTES
 
1 A preliminary report of the data was given at Experimental Biology 05, April 2005, San Diego, CA [Pagliassotti, M., Wang, D. & Wei, Y. (2005) Upstream mediators of nutrient-induced JNK activation in the liver. FASEB J. 19: #850.1 (abs.)]. Back

2 Supported by a grant from the National Institutes of Health (DK47416). Back

4 Abbreviations used: ATF, activating transcription factor; F1, medium containing 8 mmol/L glucose, 1 mmol/L fructose, and 0.12% (wt:v) inulin; G, medium containing 8 mmol/L glucose and 0.12% (wt:v) inulin; GF, medium containing 8 mmol/L glucose, 1 mmol/L fructose, 0.12% (wt:v) inulin, and 28 mU inulinase; IRS, insulin receptor substrate; IRS-1307, serine 307 of IRS 1; JIP1, JNK-interacting protein-1; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK, mitogen activated protein kinase kinase; p-ATF2, phospho-activating transcription factor-2; p-ERK1/2, phospho-p42/p44 MAP kinase; p-p38, phospho-p38 MAP kinase; pY, phosphotyrosine. Back

Manuscript received 17 February 2005. Initial review completed 26 March 2005. Revision accepted 20 April 2005.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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