Chronic kidney disease on hemodialysis is associated with decreased serum PCSK9 levels

Objectives

Serum low density lipoprotein-cholesterol (LDL-C) correlates positively with serum PCSK9 in the general population, consistent with PCSK9 being a determinant of LDL-C levels. Patients with chronic kidney disease (CKD) on hemodialysis (HD) have lower total cholesterol (TC) and LDL-C compared to the general population. Serum PCSK9 and its relationship with serum lipids have not been reported in CKD patients on HD (CKD-HD).

Methods

We measured serum PCSK9 by ELISA and lipid levels in 66 CKD-HD patients and compared them to 178 non-CKD subjects. Since statins increase serum PCSK9 levels, CKD-HD patients were separated into those not on statin therapy (HD-NS, n = 32) and those taking statins (HD-S, n = 34). No control subjects were on statin therapy.

Results

Serum PCSK9, TC, LDL-C and HDL-C levels were significantly lower in the CKD-HD group (n = 66) compared to the control group. HD-NS patients showed lower PCSK9, TC and LDL-C levels than control subjects and PCSK9 levels correlated with TC and LDL-C levels (r = 0.35, p = 0.050; r = 0.423, p = 0.0158 respectively) as well as TG levels (r = 0.413, p = 0.0188). In HD-S patients, PCSK9 levels were not significantly different from the non-CKD group. There was no correlation between PCSK9 levels and TC and LDL-C levels in the HD-S group.

Conclusion

Our data are the first quantitative analysis of serum PCSK9 levels in CKD-HD patients. We show that serum PCSK9 in HD-NS patients is decreased and it retains a positive correlation with LDL-C, suggesting that PCSK9 may remain a significant determinant of LDL-C in CKD-HD subjects. We also show that statin therapy disrupts the correlation between LDL-C and PCSK9 in CKD-HD patients. These data suggest that the regulation of LDL-C by PCSK9 remains intact in CKD-HD patients. PCSK9 may also play a role in the metabolism of triglyceride-rich lipoproteins in CKD-HD patients.     

Sorting an LDL receptor with bound PCSK9 to intracellular degradation

Objective

This article reviews the mechanism by which the low density lipoprotein receptor (LDLR) that has bound proprotein convertase subtilisin/kexin type 9 (PCSK9), is rerouted to intracellular degradation instead of being recycled.

Methods

A search of relevant published literature has been conducted.

Results

PCSK9 binds to the LDLR at the cell surface. It is the catalytic domain of PCSK9 that binds to the epidermal growth factor repeat A of the LDLR. The LDLR:PCSK9 complex is internalized through clathrin-mediated endocytosis. Due to an additional electrostatic interaction at acidic pH between the C-terminal domain of PCSK9 and the ligand-binding domain of the LDLR, PCSK9 remains bound to the LDLR in the sorting endosome. As a consequence, the LDLR fails to adopt a closed conformation and is degraded instead of being recycled. The mechanism for the failure of the LDLR to recycle appears to involve ectodomain cleavage of the extended LDLR by a cysteine cathepsin in the sorting endosome. The cleaved LDLR ectodomain will be confined to the vesicular part of the sorting endosome for degradation in the endosomal/lysosomal tract.

Conclusion

Ectodomain cleavage of an LDLR with bound PCSK9 in the sorting endosome disrupts the normal recycling of the LDLR.     

Roux-en-Y gastric bypass,but not sleeve gastrectomy,decreases plasma PCSK9 levels in morbidly obese patients

AimProprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters.MethodsFasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium).ResultsA total of 156 patients (34 SG, 122 RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (−19.6%, −16.6% and −19.5%, respectively; P < 0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r = 0.22, P = 0.007), HOMA-IR (r = 0.24, P = 0.005), total cholesterol (r = 0.17, P = 0.037) and non-HDL-C (r = 0.17, P = 0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss.ConclusionRYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.     

Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: Effects of LDL lowering by ezetimibe in the absence of statins

Objectives

To assess the lipid-lowering efficacy of ezetimibe in dyslipidemic cynomolgus monkeys comparing two dosing methods, and to evaluate PCSK9 plasma levels during dyslipidemia induction by feeding a high-fat/high-cholesterol diet (HFD), ezetimibe (Zetia^®, Ezetrol^®) treatment, ezetimibe washout, and HFD washout.

Methods and results

Twenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100–400 mg/dL) were randomized into two groups and treated with ezetimibe for two weeks, either by oral gavage or by using food treats. The lipid-lowering effects of ezetimibe were identical between the two groups. After treatment, mean LDL cholesterol was decreased by 58% (174–72 mg/dL), total cholesterol by 42% (241–138 mg/dL), and PCSK9 levels were increased by 137% (147–314 ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol.

Conclusions

In a cynomolgus dyslipidemia model, PCSK9 levels are inversely correlated with LDL cholesterol in the absence of statin treatment, regardless whether lipid changes are modulated by diet or ezetimibe treatment.     

Relationship between PCSK9 and endothelial function in patients with acute myocardial infarction

Background and aimsWhile the role of PCSK9 in lipid metabolism is well established, its link with endothelial function is less clear. The aim of the present study is to evaluate the relationship between PCSK9 and endothelial dysfunction in the setting of acute myocardial infarction.Methods and resultsTo this purpose, we analyzed the serum of 74 patients with ST-elevation myocardial infarction (STEMI) at the time of admission and after 5 days. Endothelial dysfunction was evaluated as rate of apoptosis (AR) of human umbilical vein endothelial cells incubated with patients’ serum. There was a good correlation between PCSK9 and the apoptosis rate values, both at baseline (r = 0.649) and 5-day (r = 0.648). In the 5 days after STEMI, PCSK9 increased significantly (242–327 ng/ml, p < 0.001), while AR did not (p = 0.491). Overall, 21 (28%) patients showed a reduction of PCSK9, and they had a significantly higher decrease of AR as compared to others (?13.87 vs 5.8%, p = 0.002). At the univariable analysis, the 5-day change of PCSK9 resulted to be the only variable associated with the 5-day change of the apoptosis rate (beta 0.217, 95%CI 0.091–0.344, p = 0.001).ConclusionThe variation of endothelial function and PCKS9 in the first days after an acute myocardial infarction are related. Further validation and research are necessary to confirm our findings.Clinical trialNCT02438085.     

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance,Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)].Methods: In Uku town, 674 residents (mean age; 69.2 ± 8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose × insulin levels/405.Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49–601) ng/mL and 60 (1–107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p = 0.028), triglycerides (p < 0.001), and HOMA-IR (p < 0.001), but not with LDL-C (p = 0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p < 0.001), Lp(a) (p = 0.033) and HOMA-IR (p = 0.041).Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.     

PCSK9 levels do not predict severity and recurrence of cardiovascular events in patients with acute myocardial infarction

Background and aimsIt remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up.Methods and resultsFrom September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP >10 mg/L (p < 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up.ConclusionsIn this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited.     

Effects of preadipocytes derived from mice fed with high fat diet on the angiogenic potential of endothelial cells

Background and aims

Obesity promotes a persistent inflammatory process in the adipose tissue, activating the endothelium and leading to vascular dysfunction. Preadipocytes can interact with endothelial cells in a paracrine way stimulating angiogenesis. However, the potential of preadipocytes from adipose tissue of high fat diet (HFD) fed animal to stimulate angiogenesis has not been evaluated yet. The aim of this study was to investigate the effects of such diet on the angiogenic potential of preadipocytes in a mice model.

Melatonin effect on rat body weight regulation in response to high-fat diet at middle age

We previously demonstrated that daily melatonin administration to middle-aged rats to restore youthful plasma melatonin levels also decreased body weight, visceral fat, plasma leptin, and plasma insulin to more youthful levels, without detectable changes in consumption of chow diet. We now evaluate: (a) whether melatonin alters consumption of a more precisely quantifiable liquid diet similar in high-fat content to the typical American diet; (b) differences between melatonin-induced endocrine responses in the fasted vs fed state; and (c) time course of these responses. Ten-month-old male Sprague- Dawley rats received liquid diet containing either 0.2 μg/mL melatonin (MELATONIN) or vehicle (CONTROL) (n=14/treatment); the diet was available throughout each night, but was removed for the final 10 h of each daytime. MELATONIN rats gained 4% body weight during the first 2 wk and then stabilized, whereas CONTROL rats continued to gain for an additional week, achieving 8% gain (p<0.05 vs MELATONIN). During the first 3 wk, afternoon tail-blood leptin, but not insulin, levels decreased in melatonin-treated rats (p<0.05 vs CONTROL). After 8 wk, half of the rats were killed at the midpoint of the dark period (NIGHT; fed) and half at the end of the light period (DAYTIME; fasted). NIGHT but not DAYTIME plasma leptin levels were decreased in MELATONIN rats, whereas DAYTIME but not NIGHT plasma insulin levels were decreased (p<0.05 vs CONTROL). Melatonin treatment did not alter cumulative food consumption. Thus, melatonin decreased weight gain in response to high-fat diet, decreased plasma leptin levels within 3 wk—before decreasing plasma insulin—and exerted these metabolic effects independent of total food consumption.     

高脂饲料诱导的胰岛素抵抗大鼠骨骼肌已糖胺通路流量的变化

目的 探讨已糖胺通路(HBP)在高脂饲料诱导胰岛素抵抗形成中的作用.方法 雄性SD大鼠随机分为3组:对照组、高脂组和罗格列酮组.13周后,检测大鼠血清甘油三酯(TG)、总胆固醇(TC)、游离脂肪酸(FFA)、骨骼肌中TG和FFA的含量,胰岛素敏感性采用胰岛素敏感指数(ISI)和高胰岛素正糖钳夹试验稳态时的葡萄糖输注率(GIR)来评估,骨骼肌HBP的流量用谷氨酰胺:6-磷酸果糖转氨酶(GFAT)mRNA的表达水平、二磷酸尿嘧啶-N-乙酰葡萄糖胺(UDP-GlcNAc)的含量及蛋白O-GIcNAc糖基化水平来衡量.结果 高脂组大鼠与对照组相比,血清TG、TC、FFA以及骨骼肌TG、FFA均升高(均P<0.01);ISI、GIR均降低(均P<0.01),骨骼肌GFAT mRNA的表达(0.51±0.05对0.18±0.02)、UDP-GlcNAc 含量[(6.18±0.86对2.42±0.36)nmol/g]以及蛋白O-GlcNAc糖基化水平均明显升高(均P<0.01).罗格列酮组大鼠与高脂组相比,血清和骨骼肌TG、FFA明显降低(均P<0.01),胰岛素敏感性提高(P<0.05),GFAT mRNA的表达(0.27±0.03)、UDP-GlcNAc含量[(2.62±0.32)nmol/g]以及蛋白O-GIeNAc糖基化水平均明显降低(均P<0.05).结论 高脂饲料诱导大鼠胰岛素抵抗与其增加骨骼肌HBP的流量相关,可被罗格列酮降低.     

熊去氧胆酸对高脂饮食大鼠脂肪性肝炎形成的影响

目的 探讨熊去氧胆酸对高脂馀食诱发的大鼠非酒精性脂肪性肝炎模型形成的影响。方法 29只SD大鼠随机分为3组：模型组予高脂饮食饲养;治疗组在高脂饮食饲养2周后同时加用熊去氧胆酸;正常组予标准饮食饲养,12周处死,结果 所有造模大鼠均出现肥胖、高脂血症和血清转氨酶升高,伴典型的脂肪性肝炎;与模型组相比,治疗组仅血清转氨酶、肝组织脂肪变和炎症坏死等指标有改善趋势,但两组间并无统计学差异。结论 熊去氧胆酸对高脂饮食诱发的肥胖、高脂血症性脂肪性肝炎可能并无防治作用。     

Augmented reduction of islet β‐cell mass in Goto‐Kakizaki rats fed high‐fat diet and its suppression by pitavastatin treatment

Aims/Introduction: High fat diet (HFD) is known to be a risk for development of type 2 diabetes. It is unclear, however, how it affects the glucose tolerance or the islet structure in type 2 diabetes. The aim of this study is: (i) to examine the effects of HFD on the islet in GK rats, non‐obese type 2 diabetic model; and (ii) to explore if pitavastatin treatment influences the change. Materials and Methods: To see the effects of HFD on islet changes in type 2 diabetes, 4‐week old male GK and Wistar rats were fed HFD for 16 weeks and subjected to glucose tolerance tests and pathological studies of the islet. The effects of pitavastatin (3 mg/kg/day for 16 weeks, oral), one of the lipophilc statins, were also examined in both GK and Wistrar rats fed with or without HFD. Results: The HFD induced hyperlipidemia and aggravated glucose intolerance in both GK and Wistar rats. Pitavastatin treatment did not influence the glucose tolerance in HFD‐fed animals. HFD caused an increase in hepatic lipid contents in all the animals, which was partially suppressed by pitavastatin treatment. GK rats showed reduced β‐cell mass, and fibrosis and macrophage migration in the islets. HFD feeding in GK rats augmented these changes which were associated with enhanced expression of 8‐hydroxydeoxyguanosine and an increase in apoptotic cells. Pitavastatin treatment improved the HFD‐induced islet pathology, and pancreatic insulin contents paralleled the structural changes. Conclusions: HFD feeding worsened the islet pathology in GK rats which was suppressed by pitavastatin treatment. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00173.x, 2011)     

Diallyl disulfide improves lipid metabolism by inhibiting PCSK9 expression and increasing LDL uptake via PI3K/Akt-SREBP2 pathway in HepG2 cells

Background and aimDiallyl disulfide (DADS), a volatile sulfide extracted from garlic, has been suggested as a chemical of anti-atherosclerotic drugs, while its molecular mechanism for this benefit has not fully been understood. The aim of the present study was to investigate the effects of DADS on lipid metabolism and its potential mechanisms in HepG2 cells induced by lipopolysaccharides (LPS).Methods and resultsHepG2 cells were treated with LPS with or without different concentrations of DADS (0, 20, 40, 80, 160 μg/ml) for 24 h. The cell activity was detected by CCK8, and Dil-LDL uptake assay was used to examine the LDL uptake. Real-time PCR and Western blot were used to detect the expression of LDLR, PCSK9 SREBP2 and HMGCR. In addition, we examined the effect of the combination of DADS with atorvastatin on PCSK9 expression. The results showed that LPS significantly increased PCSK9 and SREBP2 expressions in a dose-dependent manner in HepG2 cells. DADS attenuated PCSK9, SREBP2 and HMGCR expressions and up-regulated the expression of LDLR. Moreover, DADS reversed the expressions of PCSK9, SREBP2, HMGCR and LDLR induced by LPS and DADS could promote the LDL uptake in HepG2 cells. Furthermore, DADS decreased the expression of PCSK9 by activating the PI3K/Akt-SREBP2 signal pathway. Notably, DADS could reduce PCSK9 expression induced by atorvastatin in HepG2 cells.ConclusionDADS could significantly attenuated PCSK9 expression in a dose-dependent manner induced by LPS and increased the LDLR expression in HepG2 cells, which was associated with the activation of PI3K/Akt-SREBP2 signaling pathway.     

Positive correlation between plasma PCSK9 and tissue factors levels in patients with angiographically diagnosed coronary artery disease and diabetes mellitus

Background Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that influences plasma levels of low-density lipoprotein cholesterol (LDL-C). Both oxidized LDL and tissue factor (TF) contributed to the development of prothrombotic state. The present study aims to explore the relationship between plasma level of PCSK9 and that of TF in patient with coronary artery disease (CAD). Methods From July 2013 to March 2014, we enrolled 197 consecutive patients who underwent coronary angiography because of suspected CAD at Beijing Anzhen Hospital in this study. All patients had no history of using lipid-lowering medication. Of these 197 patients (131 male and 66 female, mean age 56.9 ± 11.8 years), 81 had angiographically diagnosed CAD. Clinical data were collected. Plasma PCSK9 and TF were measured using enzyme-linked immunosorbent assay (ELISA). Levels of plasma PCSK9 and TF were compared and their correlation analyzed among different patient groups. Results Both plasma levels of PCSK9 (279.8 ± 60.4 μg/L vs. 216.5 ± 45.3 μg/L, P < 0.01) and TF (156.4 ± 26.6 μg/mL vs. 112.1 ± 38.3 μg/L, P < 0.01) were significantly higher in patients with CAD, as compared with those with?out CAD. Correlation analysis showed plasma level of PCSK9 was significantly correlated with that of TF in both patients with and without CAD. However, multivariate regression analysis after adjustment for age, gender, smoking, alcohol, hypertension and hyperlipidemia showed that only in CAD patients with type 2 diabetes mellitus, there was significant positive correlation between plasma levels of PCSK9 and TF (β = 0.353, P < 0.01). Conclusions The plasma level of PCSK9 is independently and positively associated with that of TF in CAD patients with diabetes mellitus, but not in those without diabetes mellitus. Further study is needed to investigate the underlying mechanism.     

Addition of fish oil to atherogenic high fat diet inhibited atherogenesis while olive oil did not,in LDL receptor KO mice

Background and aimsMediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet.Methods and resultsForty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed).Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1).ConclusionThese results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.     

不同饥饿时段对常规及高脂饮食大鼠胃壁组织胃促生长素(ghrelin)表达的影响

目的探讨不同饥饿时段及长期高脂饮食对大鼠胃壁组织胃促生长素(ghrelin)表达的影响。方法应用Northern印迹法观察不同饥饿时段及长期高脂饮食时大鼠胃壁组织ghrelin表达的变化。结果在常规饮食喂养大鼠饥饿72 h以内(短期饥饿),其胃壁组织ghrelin表达升高(24 hP<0.05,72 hP<0.01),饥饿持续时间达120 h(长期饥饿)时,大鼠胃壁组织ghrelin表达又下调(P<0.01),但长期高脂饮食喂养的肥胖的大鼠模型,其胃壁组织ghrelin表达不受饥饿时段的影响。此外,在非饥饿状态,高脂大鼠胃壁组织ghrelin表达低于常规饮食组(P<0.01)。结论常规饮食大鼠ghrelin表达随饥饿时段延长先升后降;高脂组ghrelin表达不随饥饿时段而改变。推测肥胖时Ghrelin表达的下降及不受饥饿时段的影响可能是机体自发降低食欲,控制体重增加的机制之一。     

CCl4‐induced hepatic injury in mice fed a Western diet is associated with blunted healing

Background and Aims: Feeding a Western diet (WD) enriched in saturated fat protects against chronic alcoholic hepatitis. However, saturated fat induces lipotoxicity in cultured hepatocytes. The purpose of the present study was to elucidate the influence of WD on acute hepatic injury and healing. Methods: Male C57BL/6 mice were fed a purified control diet (CD) or WD enriched in palmitate and cholesterol. After 3 weeks, carbon tetrachloride (CCl₄) was administered (0.1 µL/g, intraperitoneally). Hepatic inflammation and proliferation were assessed by immunostaining for neutrophils and intracellular adhesion molecule‐1, and Ki67, respectively. Cytokine expression was analyzed by real‐time polymerase chain reaction. Protein levels of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) were assessed by western blotting. Results: Feeding a WD resulted in markedly greater histological evidence of necrosis and enhanced alanine aminotransferase activity (188 ± 6.2 U/L) compared to CD‐fed mice (99.1 ± 6.3 U/L) by day 2 post‐CCl₄. In contrast, WD blunted leukocyte accumulation in necrotic areas and the expression of cytokines (tumor necrosis factor‐α and interleukin‐6) involved in tissue regeneration. Diminished repair was further indexed by lower collagen‐αI and Ki67 expression in the mice fed a WD. Finally, feeding a WD, as well as the treatment of cultured hepatocytes with palmitic acid, upregulated the expression of PPAR‐γ, which has been previously shown to prevent hepatic repair following CCl₄ exposure. Conclusions: These findings suggest that impaired healing in WD‐fed mice blunted recovery from acute injury and underscored the complex relationship between diet and hepatic injury.