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. 2023 Jul 3;37(4):1609–1618. doi: 10.21873/invivo.13246

Octanoic Acid-rich Enteral Nutrition Alleviated Acute Liver Injury Through PPARγ/STAT-1/ MyD88 Pathway in Endotoxemic Rats

JIABAO TANG 1,#, XIAOHUA LI 2,#, WEI LI 1, CHUN CAO 1
PMCID: PMC10347904  PMID: 37369501

Abstract

Background/Aim: Acute liver injury is the hallmark of organ failure in sepsis. Enteral nutrition (EN) is an important clinical therapeutic measure in septic patients. However, the therapeutic effect of EN alone is not obvious. Here, we investigated whether octanoic acid (OA)-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.

Materials and Methods: First, rats were randomly divided into four groups: Sham, Lipopolysaccharide (LPS), LPS+EN and LPS+EN+OA groups to investigate the effect of OA-rich EN on LPS-induced acute liver injury in endotoxemic rats. Then rats were randomly divided into five groups: Sham, LPS, LPS+EN+OA, LPS+EN+OA+SR202 (SR) and LPS+ pioglitazone (PI) groups to examine whether OA-rich EN alleviated acute liver injury through the PPARγ/STAT-1/MyD88 pathway. Rats received nutrition support via a gastric tube for 3 days. We evaluated the liver histology, apoptosis, liver enzymes and inflammatory cytokine levels in the liver and serum. PPARγ/STAT-1/MyD88 pathway was also measured.

Results: OA-rich EN inhibited the phosphorylation of STAT-1 and the activity of MyD88 by activating PPARγ and alleviating LPS-induced acute liver injury more effectively than EN alone in endotoxemic rats. The use of SR counteracted the effect of OA-rich EN on acute liver injury. Meanwhile, PI showed effects similar to OA-rich EN in endotoxemic rats.

Conclusion: OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.

Keywords: Acute liver injury, endotoxemia, octanoic acid, enteral nutrition, PPARγ/STAT-1/MyD88 pathway

Sepsis, which is caused by the dysregulation of the host’s response to infection, leads to a series of systemic proinflammatory reactions and high mortality (1). As an important immune organ, the liver not only plays a role in immune defense during sepsis, but also is the target of inflammatory cytokines. The inflammatory response could induce liver injury and liver failure in septic patients (2). Alleviating liver injury and restoring liver function could reverse the disease development and death process of septic patients (3). As an important form of treatment in the acute stage of sepsis, early enteral nutrition (EN) could maintain gut epithelial barrier tight junction and barrier function, stimulate immunity, and reduce inflammation (4). In addition, EN could reduce complications and prolong survival in patients with liver diseases (5).

Medium chain fatty acids (MCFAs) are saturated 6-12 carbon fatty acids (FAs) that are combined with glycerol to form medium chain triglycerides, which is an important component of EN. Many studies demonstrated that EN rich in medium-chain triglycerides could alleviate chemo-induced colitis by reducing proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (6). MCFAs could also enter mitochondria in a carnitine independent manner, which increases the respiratory capacity of mitochondria in cells to promote the recovery of dysfunction during sepsis (7). octanoic acid (OA), as a member of MCFAs, also plays an important role in inflammatory response and lipid metabolism by inhibiting TLR4/NF-ĸB pathway and upregulating ABCA1/p-JAK2/p-STAT3 pathway (8,9). In addition, our previous study showed that EN rich in OA could alleviate acute liver injury during sepsis (10). However, its potential mechanism was not clarified.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor family, which includes the following three subtypes: PPARα, PPARβ and PPARγ (11,12). These nuclear receptors could be bound to specific DNA elements to participate in energy metabolism and reduce inflammation (13). PPARγ, as a ligand-induced transcription factor, has significant anti-inflammatory properties, which could transform human monocytes into M2 macrophages with anti-inflammatory properties and inhibit inflammatory pathways, such as STAT-1, AP-1 and NF-ĸB (14,15). PPARγ could also protect against acute liver injury caused by sepsis by promoting the expression of Nrf2 (16). A recent study found that MCFAs could partially activate and bind to PPARγ to regulate fat homeostasis (17).

Therefore, we investigated whether OA-rich EN alleviates acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.

Materials and Methods

Animals. A total of fifty-four Sprague-Dawley rats with an initial weight range of 236-295g were used in this study. Before the experiment, rats received standard food and water without restriction. The animal research ethics committee (Soochow University, Suzhou, Jiangsu, China) approved this study protocol.

Experimental protocol. To investigate the effect of OA-rich EN on LPS-induced acute liver injury, twenty-four rats were divided into four groups. All rats received EN using a gastric tube as described previously (18). Then rats in the Sham group were intraperitoneally (i.p.) injected with saline, and rats in the other three groups were i.p. injected with LPS (5 mg/kg, Sigma-Aldrich, St. Louis, MO, USA) to establish the model of endotoxemia. Sham and LPS groups were fed with water and standard food. To provide rats with the same total energy [100 kcal/(kg/day)], those in the LPS+EN and LPS+EN+OA groups received EN solution (Ensure Nutrison®, Abbott, Chicago, IL, USA) or OA-rich EN [0.5 g/(kg/day) of OA and 95.5 kcal/(kg/day) of EN solutions] through the gastric tube, respectively.

In addition, we explored the potential mechanism of OA-rich EN in alleviating acute liver injury. Thirty rats were divided into five groups. The Sham, LPS and LPS+EN+OA treatment groups were the same as the first part of the study. Rats in LPS+EN+OA+SR202 (SR) group were i.p. injected with SR202 (3 mg/kg) to inhibit the activity of PPARγ, and rats in LPS+pioglitazone (PI) group were i.p. injected with pioglitazone (20 mg/kg) to stimulate the activity of PPARγ. With the administration of nutritional support for 3 days, rats were sacrificed to obtain liver tissues and sera.

Histopathological evaluation. The liver tissues were fixed with 10% formalin for twenty-four hours. After embedding in paraffin, 5 μm thick sections were prepared with microtome and stained with hematoxylin-eosin (H&E). To evaluate histopathological damage, the images of each section were captured using a light microscope. The degree of pathological damage was assessed by a pathologist.

Terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Sections were washed in phosphate-buffered saline (PBS) for 30 min at 37˚C and incubated with proteinase K for 30 min at 37˚C. Subsequently, the sections were rinsed in PBS, treated with TUNEL reaction mixture containing terminal deoxynucleotidyl transferase in a humidified chamber at 37˚C for 60 min in the dark, washed with PBS and blocked in blocking buffer containing avidin-FITC for 30 min at 37˚C in the dark. The sections were then washed in PBS in the dark and glass cover slipped and examined under a fluorescent microscope.

Determination of biochemical indexes. After blood samples were taken from the inferior vena cava of rats, the serum was obtained by centrifugation. Then, the automatic biochemical analyzer SYSMEX (SYSMEX, Kobe, Japan) was used to measure the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH).

Inflammatory cytokines measurements. ELISA kits (RayBiotech, Atlanta, GA, USA) were used to measure IL-6, IL-1β, and TNF- α levels in the liver and serum.

Western blotting analysis. The collected liver tissue samples were grinded at a low temperature, and then lysed in a RIPA lysis buffer containing a protease inhibitor to extract proteins. The proteins of each experimental group were electrophoresed for 2 h at 90 V at room temperature. The samples were then transferred to polyvinylidene fluoride (PVDF) membranes for 90 min at 120 V at low temperature using transfer buffer. After the PVDF membranes were blocked with 5% skim milk, they were exposed to the primary antibody (PPARγ, p-STAT, STAT-1, MyD88, β-Actin) at 4˚C overnight. After washing the thrice with TBST, the PVDF membranes were incubated with the secondary antibody for one hour. After being treated with the ECL chemiluminescent agent, the PVDF membranes were exposed, and the results were scanned and recorded.

Statistical analysis. The data were analyzed using SPSS version 26.0 software (SPSS Inc., Chicago, IL, USA) and presented as the mean±standard error. ANOVA followed by post-hoc test was used to assess the differences between two groups. A p-value <0.05 was considered to indicate statistical significance.

Results

OA-rich EN alleviated LPS-induced acute liver injury. To investigate whether OA-rich EN played a therapeutic role in acute liver injury, we evaluated the liver histology, apoptosis of liver cells and liver enzyme levels (Figure 1). Histopathological sections in the LPS group showed hepatocyte degeneration and necrosis, inflammatory infiltration, and hepatic cord disorganization. The liver cell apoptosis and enzyme levels were significantly increased in the LPS group. Treatment of endotoxemic rats with EN and OA-rich EN resulted in decreased levels of liver enzymes, apoptosis of liver cells and liver tissue necrosis and degeneration, especially in the OA-rich EN group. Moreover, we evaluated the levels of inflammatory factors in the liver and serum (Figure 2). The levels of inflammatory factors increased in the LPS group. There was a significant decrease in inflammatory cytokines in LPS+EN and LPS+EN+OA groups compared with the LPS group, and the decrease was most pronounced in the LPS+EN+OA group. Therefore, we suggest that OA-rich EN alleviates LPS-induced acute liver injury more effectively than EN alone.

Figure 1. Octanoic acid (OA)-rich enteral nutrition (EN) alleviated lipopolysaccharide (LPS)-induced acute liver injury. Hematoxylin-eosin staining of liver tissue (A) was used to obtain representative histological images and pathological scores (C). Liver apoptosis (B) was measured using TUNEL and the levels of aspartate aminotransferase (AST) (D), alanine aminotransferase (ALT) (E) and lactate dehydrogenase (LDH) (F) were measured using an automatic biochemical analyzer. Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the LPS group. ^p<0.05 versus the LPS+EN group.

Figure 1

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Figure 2. Octanoic acid (OA)-rich enteral nutrition (EN) reduced the levels of inflammatory factors. The levels of inflammatory cytokines IL-6, IL1β and TNF-α in the serum (A-C) and liver (D-F) were measured with the ELISA kits. Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the LPS group. ^p<0.05 versus the lipopolysaccharide (LPS)+EN group.

Figure 2

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OA-rich EN enhanced PPARγ/STAT-1/MyD88 pathway. To further explore the molecular mechanism of OA-rich EN in LPS-induced acute liver injury, we evaluated the expression of related proteins in the liver tissues using western blotting (Figure 3). The result showed that the LPS group enhanced the expression of PPARγ compared with the Sham group. Meanwhile, the expression of p-STAT-1 and MyD88, as the downstream effectors of PPARγ, were significantly increased while the expression of STAT-1 was not altered. Treatment of endotoxemic rats with EN and OA-rich EN resulted in further increase in the expression of PPARγ. Furthermore, it prevented the increase in the expression of p-STAT-1 and MyD88. Compared with the LPS+EN group, the expression of PPARγ was higher and that of p-STAT-1 and MyD88 were lower in the LPS+EN+OA group. The above findings demonstrate that OA-rich EN alleviates LPS-induced acute liver injury by enhancing the expression of PPARγ.

Figure 3. Octanoic acid (OA)-rich enteral nutrition (EN) enhanced the PPARγ/STAT-1/MyD88 pathway. The expression levels of PPARγ, p-STAT-1, STAT-1, MyD88 were analyzed using western blot (A). β-actin was used as internal reference. Quantitative analysis of protein expression is shown in (B-E). Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the LPS group. ^p<0.05 versus the lipopolysaccharide (LPS)+EN group.

Figure 3

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Then LPS-induced and EN+OA-treated rats were i.p. injected with SR202 (LPS+EN+OA+SR group) to inhibit the activity of PPARγ. This treatment reduced the effect of OA-rich EN. The expression of PPARγ was decreased and the expression of STAT-1 and MyD88 were increased in the LPS+EN+OA +SR group. In addition, LPS-treated rats were i.p. injected with PI (LPS+PI group) to enhance PPARγ activity, and the results showed that PI had effects similar to those of OA-rich EN. The expression of PPARγ was increased and the expression of STAT-1 and MyD88 were decreased in the LPS+PI group. These results showed that OA-rich EN could prevent STAT-1 phosphorylation by enhancing PPARγ activity, thereby inhibiting MyD88 expression (Figure 4).

Figure 4. Octanoic acid (OA)-rich enteral nutrition (EN) prevented STAT-1 phosphorylation by enhancing PPARγ activity, thereby inhibiting MyD88 expression. The expression of PPARγ, p-STAT-1, STAT-1, MyD88 was analyzed using western blot (A). β-actin was used as internal reference. Quantitative analysis of protein expression is shown in (B-E). Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the LPS group. ^p<0.05 versus the lipopolysaccharide (LPS)+EN+OA group. SR: SR202; PI: pioglitazone.

Figure 4

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OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway. Figure 5 shows that the administration of SR weakened the effect of OA-rich EN. The liver enzyme levels, and apoptosis were increased in the LPS+EN+OA+SR group, Whereas the administration of PI showed an effect similar to that of OA-rich EN. Meanwhile, the administration of SR increased the levels of inflammatory factors in the liver and serum, whereas PI showed the opposite effects (Figure 6). Therefore, OA-rich EN alleviates acute liver injury through PPARγ/STAT-1/MyD88 pathway.

Figure 5. Octanoic acid (OA)-rich enteral nutrition (EN) alleviated acute liver injury through the PPARγ/STAT-1/MyD88 pathway. Hematoxylineosin staining of liver tissue (A) was used to obtain representative histological images and pathological scores (C). Liver apoptosis (B) was measured with TUNEL and the levels of aspartate aminotransferase (AST) (D), alanine aminotransferase (ALT) (E) and lipopolysaccharide (LDH) (F) were measured using an automatic biochemical analyzer. Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the LPS group. ^p<0.05 versus the LPS+EN+OA group. SR: SR202; PI: pioglitazone.

Figure 5

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Figure 6. Octanoic acid (OA)-rich enteral nutrition (EN) reduced the levels of inflammatory factors through the PPARγ/STAT-1/MyD88 pathway. The levels of inflammatory cytokines IL-6, IL1β and TNF-α in the serum (A-C) and liver (D-F) were measured using ELISA kits. Data are presented as mean±SEM (n=6 per group). *p<0.05 versus the Sham group. #p<0.05 versus the lipopolysaccharide (LPS) group. ^p<0.05 versus the LPS+EN+OA group. SR: SR202; PI: pioglitazone.

Figure 6

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Discussion

Acute liver injury is the hallmark organ failure in sepsis. Septic patients are likely to have lower morbidity and mortality when liver injury and damage are prevented (3). An excessive inflammatory response in the acute stage of sepsis is a critical pathogenesis of acute liver injury in septic patients (2). As an important therapy for sepsis, EN provides sufficient protein and calories for septic patients to avoid muscle atrophy and metabolic disorders (19). The survival of critically ill patients could be improved with the administration of EN within 24 h of admission to the intensive care unit (20). However, the therapeutic effect of EN alone is not obvious. In this study, we found that OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway.

In the liver, Kupffer cells, which specialize in detecting and trapping pathogens, are present in great numbers (21). Upon LPS-induced acute liver injury, there is a massive release of proinflammatory cytokines and free radicals from activated Kupffer cells (22). The resulting inflammatory reaction inhibits the further development of inflammation but leads to liver damage (23). In this study, the fact that liver enzymes and inflammatory factors were significantly increased suggested that liver damage was indeed partially mediated by an inflammatory response. The neutrophil infiltration of the liver and increased levels of apoptosis further supported the role of inflammation in acute liver injury. It had been shown that medium-chain glycerate reduces liver damage by inhibiting inflammatory signaling pathways and counteracting apoptosis (24). The imbalance of ATP levels in the liver tissue is one of the pathological changes associated with acute liver injury. When ATP levels are reduced, classic apoptosis is prevented and necrosis becomes the main pathway of cell death, which leads to severe inflammation. Studies have shown that mitochondrial beta oxidation is compromised in acute liver failure, resulting in increased accumulation of FAs attached to carnitine molecules in the blood, along with reduced energy production (25). As the main fatty acid component of medium chain triglycerides in ketogenic diet, OA directly enters the liver through the portal vein, after being absorbed by the human body, bypassing the lymphatic system. NAD+/NADH could be improved by liver mitochondria to reduce metabolic dysfunction (26). Studies have shown that a diet rich in OA could increase the number of mitochondria and provide more energy for the body (27). In addition, OA could inhibit pathogenic bacteria such as Escherichia coli and improve intestinal barrier function and antioxidant capacity (28). OA could also reduce oxidative stress by enhancing the activity of antioxidant enzymes, thus protecting the liver (29). Our results indicated that OA-rich EN further improved the histopathological scores of liver and reduced the levels of apoptosis, inflammatory cytokines, and liver enzymes compared to EN alone.

Dysregulation of MyD88 activated pro-inflammatory cascades and MyD88-targeted therapeutic intervention could relieve the inflammatory reaction (30). Studies have shown that the use of MyD88 inhibitor could inhibit the inflammatory factors released by peripheral blood mononuclear cells, thus reducing inflammation (31). LPS-induced inflammatory cytokine transcription and protein production could be inhibited and the liver could be protected by decreasing the expression of MyD88. However, when MYD88 was specifically knocked out of the liver, the rats were predisposed to glucose intolerance, inflammation, and hepatic insulin resistance (32). Our study found that OA-rich EN could increase the expression of PPARγ and decrease the expression of MyD88, thereby alleviating acute liver injury in endotoxemic rats. As an upstream signalling factor of MyD88, PPARγ plays an important role in inflammation and fibrosis in organs, such as the kidney, colon, and pancreas (33). The effect of PPARγ activation on hepatocytes has previously been investigated using in vivo and in vitro inflammatory models. In one of these studies, the activation of PPARγ reduced IL-6, IL-1β expression and neutrophil infiltration (34). PPARγ also induced the activation and polarization of macrophages, inhibited the activation of dendritic cells, and altered T helper cells (Th) 1/Th2 and Th17/regulatory T cells ratios (35). LPS and other bacterial toxins are recognized by the innate immune system via pathogen recognition receptors, thus activating inflammatosomes and increasing the levels of proinflammatory cytokines and leading to persistent liver inflammation (36). In addition, TLRs activate MyD88, which directly or indirectly activates NF-ĸB by phosphorylating IĸBα or activating MAPK (37). In response, PPARγ protects the liver by inhibiting transcription of inflammatory response genes and inhibiting the TLR signal in bile duct cells (38). In addition, PPARγ could inhibit the expression of MyD88 by inhibiting the phosphorylation of STAT-1 (39). Given the role of PPARγ described above, we explored whether OA-rich EN inhibited the phosphorylation of STAT-1 and the activity of MyD88 by activating PPARγ. In the first part of the study, the activity of PPARγ in the LPS group was increased. We hypothesized that it was the body’s own adaptation to external damage; the body partially resists the damage caused by LPS by increasing PPARγ activity. In addition, we found that the expression of PPARγ was increased, the phosphorylation of STAT-1 was decreased without affecting the activity of STAT-1 and the expression of MyD88 was decreased when EN and OA-rich EN were administered. To examine whether OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway we used SR, an inhibitor of PPARγ. Treatment with SR counteracted the effect of OA-rich EN on acute liver injury. Meanwhile, PI, an activator of PPARγ showed effects similar to OA-rich EN.

Conclusion

OA-rich EN alleviates acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats. Therefore, OA-rich EN may be a good nutrition support therapy for septic patients.

Funding

This study was supported by the National Natural Science Foundation of China (82202369) and the Suzhou Municipal Science and Technology Bureau (SKYD2022117).

Conflicts of Interest

The Authors have no potential conflicts of interest to report in relation to this study.

Authors’ Contributions

CC and WL supervised the entire project and designed the study. JT and XL performed the study, collected data, and conducted data analyses. CC wrote and revised the manuscript. All Authors critically reviewed and approved the final manuscript.

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