Effects of NPY-2 Receptor Antagonists, Semaglutide, PYY3-36, and Empagliflozin on Early MASLD in Diet-Induced Obese Rats.

(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.

Emerging role of ferroptosis in metabolic dysfunction-associated steatotic liver disease: revisiting hepatic lipid peroxidation.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterised by cell death of parenchymal liver cells which interact with their microenvironment to drive disease activity and liver fibrosis. The identification of the major death type could pave the way towards pharmacotherapy for MASH. To date, increasing evidence suggest a type of regulated cell death, named ferroptosis, which occurs through iron-catalysed peroxidation of polyunsaturated fatty acids (PUFA) in membrane phospholipids. Lipid peroxidation enjoys renewed interest in the light of ferroptosis, as druggable target in MASH. This review recapitulates the molecular mechanisms of ferroptosis in liver physiology, evidence for ferroptosis in human MASH and critically appraises the results of ferroptosis targeting in preclinical MASH models. Rewiring of redox, iron and PUFA metabolism in MASH creates a proferroptotic environment involved in MASH-related hepatocellular carcinoma (HCC) development. Ferroptosis induction might be a promising novel approach to eradicate HCC, while its inhibition might ameliorate MASH disease progression.

Anaerobutyricum soehngenii Reduces Hepatic Lipogenic Pathways and Increases Intestinal Gluconeogenic Gene Expression in Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD) Mice.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing health problem for which no therapy exists to date. The modulation of the gut microbiome may have treatment potential for MASLD. Here, we investigated Anaerobutyricum soehngenii, a butyrate-producing anaerobic bacterium with beneficial effects in metabolic syndrome, in a diet-induced MASLD mouse model. Male C57BL/6J mice received a Western-type high-fat diet and water with 15% fructose (WDF) to induce MASLD and were gavaged with A. soehngenii (108 or 109 colony-forming units (CFU) 3 times per week) or a placebo for 6 weeks. The A. soehngenii gavage increased the cecal butyrate concentrations. Although there was no effect on histological MASLD scores, A. soehngenii improved the glycemic response to insulin. In the liver, the WDF-associated altered expression of three genes relevant to the MASLD pathophysiology was reversed upon treatment with A. soehngenii: Lipin-1 (Lpin1), insulin-like growth factor binding protein 1 (Igfbp1) and Interleukin 1 Receptor Type 1 (Il1r1). A. soehngenii administration also increased the intestinal expression of gluconeogenesis and fructolysis genes. Although these effects did not translate into significant histological improvements in MASLD, these results provide a basis for combined gut microbial approaches to induce histological improvements in MASLD.

Effectiveness of metformin for the reversal of cold-ischemia-induced damage in hepatosteatosis.

BACKGROUND: Primary dysfunction and rejection are more common in donor liver tissues with steatosis. AMP-activated protein kinase (AMPK) assumes organ-protective functions during ischemia. Metformin was used for the activation of AMPK in hepatocytes. The aim of this study is to investigate the effectiveness of metformin administration for the reversal of cold-ischemia-induced damage in hepatosteatosis. MATERIAL AND METHODS: Seven-week-old C7BL56 male-mice (n = 109) were separated into four groups depending on diet type and metformin use. A specific diet model was followed for 10 weeks to induce hepatosteatosis. A group of the animals was administered with metformin for the last four weeks via oral gavage. After resection, the liver tissues were perfused and kept for 0-6-12-24 h in the UW solution. Histopathological examinations were performed, and Western blot was utilized to analyze p-AMPK and AMPK expression levels. RESULTS: Hepatosteatosis decreased significantly with metformin. The steatotic liver group had more prominent pericentral inflammation, necrosis as well as showing a decreased and more delayed AMPK response than the non-fat group. All these alterations could be corrected using metformin. CONCLUSION: Metformin can increase the resistance of livers with hepatosteatosis to cold-ischemia-induced damage, which in turn may pave the way for successful transplantation of fatty living-donor livers.

Chaenomeles sinensis (Thouin) Koehne fruit polyphenols alleviate high-fat diet-induced obesity and liver steatosis by improving lipid metabolism in mice.

Chaenomeles sinensis (Thouin) Koehne fruit is a rich source of medicinally and nutritionally important natural phytochemicals that benefit human health. Based on the information provided, we hypothesized that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols (CSFP) possessed in vivo protective effect of on high-fat diet (HFD)-induced obesity and hepatic steatosis. Specific pathogen-free male C57BL/6J mice were randomly divided into 3 groups and fed with a low-fat diet, HFD, or HFD supplemented with CSFP by intragastric administration for 14 weeks. Obesity-related biochemical indexes and hepatic gene expression profile were determined. The findings of this study demonstrated notable reductions in body weight gain, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and steatosis grade in the group supplemented with CSFP compared with the HFD group. Gene expression analysis provided insights into the molecular mechanisms, demonstrating that CSFP downregulated the expression of key genes involved in lipogenesis (e.g., Fas, Fads2, Scd1) and upregulated the genes associated with fatty acid oxidation (e.g., Pparα, Cpt1a, Acox1), while also suppressing genes implicated in cholesterol homeostasis (e.g., HMGCoR, Insig1, AdipoR2). These molecular changes suggest that CSFP exerts protective effects by modulating hepatic lipid metabolism pathways, thereby mitigating the metabolic derangements associated with HFD-induced obesity and hepatic steatosis.

Medium-Chain Fatty Acid Feeding Reduces Oxidation and Causes Panacinar Steatosis in Livers of Neonatal Pigs.

BACKGROUND: Medium-chain fatty acids (MCFAs) are commonly used to enhance the caloric content of infant formulas. We previously reported that pigs fed MCFA developed hepatic steatosis when compared to those fed isocaloric long-chain fatty acid (LCFA) rich formula. OBJECTIVES: The objectives of this study were to investigate: 1) whether MCFA and LCFA feeding affect hepatic fatty acid oxidation, and 2) how fat type alters the expression of hepatic fatty acid metabolic genes. METHODS: Twenty-six, 7-d-old pigs were fed a low-energy control (CONT) formula, or 2 isocaloric high-energy formulas rich in LCFA or MCFA for 22 days. Livers were collected for examining ex vivo fatty acid oxidation, fatty acid content, and mRNA expression of fatty acid metabolic genes. RESULTS: Liver fat was 20% for pigs in the MCFA compared with 2.9% and 4.6% for those in the CONT and LCFA groups (P < 0.05). MCFA-fed pigs had greater amounts of hepatic laurate, myristate, palmitate, and palmitoleate (14, 34, 49, and 9.3 mg · g-1) than those fed LCFA and CONT (1.8, 1.9, 19, 1.5 mg · g-1) formulas (P ≤ 0.05). Hepatic laurate and palmitate oxidation was reduced for pigs fed MCFA (29 mmol · mg-1 · h-1) compared with those fed CONT (54 mmol · mg-1 · h-1) and LCFA (51 mmol · mg-1 · h-1) formulas (P < 0.05). Expression of fatty acid synthase 3 (FASN-3), fatty acid binding protein 1 (FABP-1), and acetyl-CoA carboxylase 1 (ACACA-1) were 8-, 6-, and 2-fold greater for pigs in the MCFA than those in the LCFA and CONT groups (P < 0.05). CONCLUSIONS: Feeding MCFA resulted in hepatic steatosis compared with an isocaloric formula rich in LCFA. Steatosis occurred concomitantly with reduced fatty acid oxidation but greater mRNA expression of fatty acid synthetic and catabolic genes.

FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease.

BACKGROUND AND PURPOSE: Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. METHODS: The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS). RESULTS: FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. CONCLUSIONS: FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Insights into the influence of three types of sugar on goose fatty liver formation from endoplasmic reticulum stress (ERS).

This study analyzed the formation of goose fatty liver due to endoplasmic reticulum stress (ERS) caused by 3 types of sugar. Transcriptome analysis was performed for liver tissues from geese fed a traditional diet (maize flour), geese overfed with traditional diet, and geese overfed with diet supplemented with glucose, fructose, or sucrose. Correlation analysis of the liver tissue transcriptomes showed that differentially expressed genes (DEGs) involved in ERS were significantly negatively correlated with DEGs involved in inflammation response in the sucrose overfeeding group, and significantly positively correlated with the DEGs involved in lipid metabolism in fructose overfeeding group. Goose primary hepatocytes were isolated in vitro and then treated with glucose or fructose. Some were also treated with ERS inhibitor 4-phenylbutyric acid (4-PBA). In the hepatocytes, mRNA expression of X-Box Binding Protein 1 (XBP1), activating transcription factor 6 (AFT6) and glucose-regulated protein 78 (GRP78) genes increased in the two sugar groups (glucose and fructose), but were suppressed by adding 4-PBA. The mRNA expression data, protein kinase contents, and triglyceride (TG) and very low-density lipoprotein (VLDL) concentrations all suggest that ERS regulates lipid deposition induced by glucose and fructose via elevating lipid synthesis, inhibiting fatty acid oxidation, and decreasing lipid transportation. In conclusion, glucose, or fructose cause ERS and then ERS causes lipid deposition in goose primary hepatocytes. Three types of sugar cause lipid accumulation and then lipid accumulation prevents ERS during goose fatty liver formation, which suggests a potential mechanism protects goose livers from ERS. The different sugars may induce lipid deposition in different ways.

ALDH2 deficiency exacerbates MCD-diet induced MASLD by modulating bile acid metabolism.

Aldehyde dehydrogenase 2 (ALDH2), an acetaldehyde dehydrogenase in mitochondria, is primarily responsible for metabolizing alcohol-derived acetaldehyde and other endogenous aldehydes. Inactivating ALDH2 rs671 polymorphism is found in up to 8 % of the global population and 40 % of the East Asian population. Recent studies have shown that rs671 SNP mutation in the human ALDH2 gene is associated with an increased risk of metabolic dysfunction-associated steatotic liver diseases (MASLD), but the mechanism remains unclear. Here, we identify the role of ALDH2 in MASLD. Firstly, ALDH2 activity was lower in MASLD patients and the methionine-choline deficiency (MCD) diet induced MASLD model. Secondly, activation of ALDH2 activity with Alda-1 (ALDH2 agonist) attenuated MCD-diet induced hepatic triglyceride (TG) accumulation and steatosis, whereas the opposite result was observed with cyanamide (CYA, ALDH2 inhibitor). Furthermore, ALDH2 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis in the MCD-diet induced mice. RNA sequencing (RNA-seq) revealed that oxysterol 7-α hydroxylase (Cyp7b1) and the related metabolic pathway significantly changed in the MCD-diet challenged ALDH2-/- mice. In ALDH2-/- mice, the expression of Cyp7b1 was downregulated and FXR/SHP signaling was inhibited, reducing the alternative bile acid (BA) synthetic pathway. In our in vitro experiments, knockdown of ALDH2 exacerbated TG accumulation in hepatocytes, whereas the opposite result was observed with overexpression of ALDH2. Moreover, chenodeoxycholic acid (CDCA) rescued ALDH2 downregulation induced TG accumulation in hepatocytes. Our study reveals that ALDH2 attenuates hepatocyte steatosis by regulating the alternative BA synthesis pathway, and ALDH2 may serve as a potential target for the treatment of MASLD.

Interactions between Multiple Organs and Nutritional Metabolism in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Steatotic liver disease (SLD) is a condition characterized by an accumulation of fat in the liver [...].

Berberine Protects against High-Energy and Low-Protein Diet-Induced Hepatic Steatosis: Modulation of Gut Microbiota and Bile Acid Metabolism in Laying Hens.

Berberine (BBR) is a natural alkaloid with multiple biotical effects that has potential as a treatment for fatty liver hemorrhagic syndrome (FLHS). However, the mechanism underlying the protective effect of BBR against FLHS remains unclear. The present study aimed to investigate the effect of BBR on FLHS induced by a high-energy, low-protein (HELP) diet and explore the involvement of the gut microbiota and bile acid metabolism in the protective effects. A total of 90 healthy 140-day-old Hy-line laying hens were randomly divided into three groups, including a control group (fed a basic diet), a HELP group (fed a HELP diet), and a HELP+BBR group (high-energy, high-protein diet supplemented with BBR instead of maize). Our results show that BBR supplementation alleviated liver injury and hepatic steatosis in laying hens. Moreover, BBR supplementation could significantly regulate the gut's microbial composition, increasing the abundance of Actinobacteria and Romboutsia. In addition, the BBR supplement altered the profile of bile acid. Furthermore, the gut microbiota participates in bile acid metabolism, especially taurochenodeoxycholic acid and α-muricholic acid. BBR supplementation could regulate the expression of genes and proteins related to glucose metabolism, lipid synthesis (FAS, SREBP-1c), and bile acid synthesis (FXR, CYP27a1). Collectively, our findings demonstrate that BBR might be a potential feed additive for preventing FLHS by regulating the gut microbiota and bile acid metabolism.

Association between diet soft drink consumption and metabolic dysfunction-associated steatotic liver disease: findings from the NHANES.

BACKGROUND: Lifestyle change plays a crucial role in the prevention and treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). In recent years, diet soft drinks that emphasize "zero sugar and zero calories" have become all the rage, but whether diet soft drink consumption is associated with MASLD is not clear. METHODS: This study included data from the National Health and Nutrition Examination Surveys (NHANES) in 2003-2006. The assessment of MASLD status primarily relied on the Fatty Liver Index (FLI). Weighted multiple Logistic regression models were constructed to evaluate the association between diet soft drink consumption and MASLD. Additionally, mediation analysis was performed to examine the mediating effect of body mass index (BMI). RESULTS: A total of 2,378 participants were included in the study, among which 1,089 individuals had MASLD, and the weighted prevalence rate was 43.64%. After adjusting for variables related to demographic, lifestyle, and metabolic syndrome, excessive diet soft drink consumption (the "always" frequency) remained significantly associated with the occurrence of MASLD (OR = 1.98, 95%CI = 1.36-2.89, P = 0.003). It was estimated that 84.7% of the total association between diet soft drink consumption and MASLD was mediated by BMI (P < 0.001). CONCLUSIONS: Excessive diet soft drink consumption was associated with the occurrence of MASLD. BMI may play a mediating role in the association between diet soft drink consumption and MASLD.

The Fatty Liver Index, the Strongest Risk Factor for Low Testosterone Level.

INTRODUCTION: The study aimed to determine if hepatic steatosis assessed by fatty liver index (FLI) was an independent risk factor for male low testosterone level and whether the FLI was the strongest risk factor for low testosterone level in two different age groups. METHODS: Two cross-sectional studies were performed. A total of 3,443 male participants (aged 46-75) were recruited into study A (part of lONgitudinal study (REACTION)). Then a total of 267 male participants (aged 25-45) were recruited into study B. Serum total testosterone (TT) and sex hormone-binding globulin (SHBG) levels, indicators for assessing hepatic steatosis were measured. The Pearson correlation and regression analysis were performed to investigate the risk factors for low testosterone level. RESULTS: The FLI had the strongest negative correlation with serum testosterone in the study A (r = -0.436) and B (r = -0.542). Compared with patients with a FLI lower than 30, the risk for low testosterone level increased by 3.48-fold in subjects with a FLI higher than 60 adjusted for potential risk factors in study A. In study B, the odds ratio of low testosterone level in patients with potential hepatic steatosis was 4.26 (1.57-11.60) after adjusted for age and homeostasis model assessment of insulin resistance (HOMA-IR) and 0.59 (0.14-2.60) after adjusted for age, HOMA-IR, waist circumference, body mass index, and SHBG. CONCLUSIONS: FLI was the strongest risk factor for male low testosterone level independent of insulin resistance in male populations of different ages; however, the association can be modulated by SHBG levels in the young. SIGNIFICANCE STATEMENT: In the study, FLI was the strongest negative risk factor for low testosterone level in the Chinese adult male population. The results suggested that hepatic steatosis assessed by the FLI was the main risk factor for male low testosterone level, independent of age, insulin resistance, smoking, and drinking status; however, the association of FLI and TT levels can be modulated by SHBG levels. Taken together these findings indicate that clinical physicians should pay more attention to the FLI index and hepatic steatosis, so that they can take advantage of them for assessing the risk of developing of low testosterone level in the male population.

Pectic oligosaccharides ameliorate high-fat diet-induced obesity and hepatic steatosis in association with modulating gut microbiota in mice.

Accumulating evidence has shown that gut microbiota and its metabolites have important significance in the etiology of obesity and related disorders. Prebiotics prevent and alleviate obesity by modulating the gut microbiota. However, how pectin oligosaccharides (POS) derived from pectin degradation affect gut microbiota and obesity remains unclear. To investigate the potential anti-obesity effects of POS, mice were fed a high-fat diet (HFD) for 12 weeks and a POS supplement with drinking water during the last 8 weeks. The outcomes demonstrated that POS supplementation in HFD-fed mice decreased body weight (P < 0.01), improved glucose tolerance (P < 0.001), reduced fat accumulation (P < 0.0001) and hepatic steatosis, protected intestinal barrier, and reduced pro-inflammatory cytokine levels. After fecal metagenomic sequencing, the POS corrected the gut microbiota dysbiosis caused by the HFD, as shown by the increased populations of Bifidobacterium, Lactobacillus taiwanensis, and Bifidobacterium animalis, and decreased populations of Alistipes and Erysipelatoclostridium, which were previously considered harmful bacteria. Notably, the changed gut microbiota was associated with the obesity prevention of POS. These findings demonstrate that POS regulates particular gut microbiota, which is essential owing to its ability to prevent disorders associated with obesity.

Association between Alcohol Consumption and Metabolic Dysfunction-Associated Steatotic Liver Disease Based on Alcohol Flushing Response in Men: The Korea National Health and Nutrition Examination Survey 2019-2021.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is distinguished by the buildup of excessive liver fat unrelated to alcohol consumption. However, the role of alcohol consumption on disease progression is debatable. Recently, alcohol flushing syndrome in Asian populations has gained interest, and its role in the risk of developing MASLD is unknown. Therefore, in this cross-sectional study, we investigated the association between alcohol consumption and MASLD in Korean men, considering their alcohol flushing response and utilizing the lipid accumulation product (LAP) score. Data from the Korean National Health and Nutrition Examination Survey (2019-2021) were analyzed. Participants were categorized into non-or-infrequent drinkers and light-to-heavy drinkers and further sub-classified based on alcohol flushing response as non-flushers and flushers. Multivariate logistic regression analysis showed a significant association between alcohol consumption and MASLD risk in both non-flushers (aHR 1.90, 95% CI 1.51-2.40, p < 0.001) and flushers (aHR 2.35, 95% CI 1.94-2.84, p < 0.001) after adjusting for potential confounding factors such as age, exercise, smoking, body mass index, systolic blood pressure, total cholesterol, and fasting plasma glucose. There was a significant interaction between alcohol consumption and alcohol flushing response for MASLD risk (p for interaction < 0.001). These findings emphasize the importance of alcohol flushing as a potential indicator of MASLD risk in Korean men and highlight the need for further research to understand the underlying mechanisms and develop targeted preventive strategies.

Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity.

Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb-/-) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb-/-) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb-/- mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb-/- mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb-/- exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb-/- mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.

Optimal liver transplant procedure in progressive familial intrahepatic cholestasis type 1 treated with biliary diversion or intestinal transplantation: Lessons learned from three cases treated with different approaches.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an autosomal recessive cholestatic liver disorder caused by ATP8B1 gene mutations. Although liver transplantation (LT) is indicated for progressive liver disease, postoperative complications, including severe diarrhea and graft steatohepatitis leading to graft loss, have been reported. CASES: The first patient had jaundice, pruritus, diarrhea, and growth retardation (weight z-score: -2.5; height z-score: -3.7). She underwent LT with total internal biliary diversion (TIBD) to the colon at 2 years of age. Graft biopsy at the 7-year follow-up examination revealed microvesicular steatosis (60%). Her diarrhea improved, and her growth failure was recovering (weight z-score: -1.0; height z-score: -1.7). The second patient underwent sequential intestine-liver transplantation at 8 years of age due to end-stage liver disease (ESLD) and short bowel syndrome caused by massive bowel resection for internal hernia after partial external biliary diversion (PEBD) at 21 months of age. She developed severe pancreatitis induced by steroid-bolus therapy for rejection after transplantation. She died 1.7 years after intestinal transplantation due to an uncontrollable pancreatic abscess and acute respiratory distress syndrome. The third patient underwent PEBD at 15 months of age and received LT with TEBD at 15 years of age due to ESLD with hepatic encephalopathy. Throughout the perioperative period, she showed no abdominal symptoms, including diarrhea and pancreatitis. Graft biopsy at the 2-year follow-up examination revealed macrovesicular steatosis (60%) with inflammation. CONCLUSIONS: The patients showed different outcomes. Effective therapeutic options to mitigate post-LT complications in patients with PFIC1 must be considered individually.