• Cilostazol
• Hepatectomy
• Liver regeneration
• Non-alcoholic fatty liver disease
• Obesity

• Animals
• Cilostazol/pharmacology
• Liver Regeneration/drug effects
• Hepatectomy
• Fatty Liver/drug therapy
• Fatty Liver/surgery
• Fatty Liver/pathology
• Rats
• Rats, Sprague-Dawley
• Disease Models, Animal
• Male
• Liver/drug effects
• Liver/pathology
• Liver/blood supply
• Liver/surgery
• Apoptosis/drug effects
• Cell Proliferation/drug effects

• Universität des Saarlandes (1036)

• fructose
• lipogenesis
• lipophagy
• nonalcoholic fatty liver disease
• urolithin A

• Animals
• Mice
• Non-alcoholic Fatty Liver Disease/chemically induced
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Hydrolyzable Tannins
• Fructose/adverse effects
• Fructose/metabolism
• Autophagy
• Lipids

• anti-inflammation
• anti-metabolic syndrome
• anti-oxidative stress
• bioactive compounds
• cellular redox balance
• histone acetylation

• Epigenetics
• Mediterranean Diet
• Nutriepigenetics
• Polyphenols

• Humans
• Diet, Mediterranean

• hepatectomy
• liver regeneration
• liver transplantation

• Animals
• Fatty Liver/physiopathology
• Hepatectomy/methods
• Humans
• Liver/physiology
• Liver Regeneration/physiology
• Liver Transplantation/methods

• Cell growth
• Cell proliferation
• Fatty liver
• Liver protection
• Liver regeneration
• Programmed cell death

• Animals
• Cell Death
• Cell Proliferation
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Humans
• Liver/cytology
• Liver/physiology
• Liver Regeneration

Recent results from single cell gene and protein regulation studies are starting to uncover the previously underappreciated fact that individual cells within a population exhibit high variability in the expression of mRNA and proteins (i.e., molecular variability). By combining cellular network modeling, and high-throughput gene expression measurements in single cells, we seek to reconcile the high molecular variability in single cells with the relatively low variability in tissue-scale gene and protein expression and the highly coordinated functional responses of tissues to physiological challenges. In this study, we focus on relating the dynamic changes in distributions of hepatic stellate cell (HSC) functional phenotypes to the tightly regulated physiological response of liver regeneration.

We develop a mathematical model describing contributions of HSC functional phenotype populations to liver regeneration and test model predictions through isolation and transcriptional characterization of single HSCs. We identify and characterize four HSC transcriptional states contributing to liver regeneration, two of which are described for the first time in this work. We show that HSC state populations change in vivo in response to acute challenges (in this case, 70% partial hepatectomy) and chronic challenges (chronic ethanol consumption). Our results indicate that HSCs influence the dynamics of liver regeneration through steady-state tissue preconditioning prior to an acute insult and through dynamic control of cell state balances. Furthermore, our modeling approach provides a framework to understand how balances among cell states influence tissue dynamics.

Taken together, our combined modeling and experimental studies reveal novel HSC transcriptional states and indicate that baseline differences in HSC phenotypes as well as a dynamic balance of transitions between these phenotypes control liver regeneration responses.

The online version of this article (10.1186/s12918-018-0605-7) contains supplementary material, which is available to authorized users.

• Hepatic stellate cell
• High-throughput data analysis
• Liver regeneration
• Mathematical modeling
• Single cells

• cell death
• dynamic modeling
• liver failure
• liver regeneration
• liver resection
• virtual patient

• ER-stress
• Fatty Liver
• Lipid metabolism
• NAFLD
• SIRT1
• liver regeneration
• steatosis

To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH).

Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration.

The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05).

NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.

• Rat
• Non-alcoholic fatty liver
• Non-alcoholic steatohepatitis
• Liver regeneration
• Hepatectomy
• Ki-67
• Gene expression

• Non-alcoholic fatty liver disease
• crc liver metastases
• liver metastasis recurrence
• liver regeneration
• liver volumetrics
• nafld

The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation.

Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration.

C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 10⁵ MSCs or vehicle via the tail vein immediately after Hpx.

We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes.

These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice.

MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation.

The online version of this article (doi:10.1186/s13287-016-0469-y) contains supplementary material, which is available to authorized users.

• Hepatic steatosis
• Liver regeneration
• Mesenchymal stem cells
• Multipotent mesenchymal stromal cells
• Regenerative medicine

Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings.

We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis.

An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment.

The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and -SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis.

The online version of this article (doi:10.1186/s12876-016-0568-3) contains supplementary material, which is available to authorized users.

• FXR
• Liver injury
• Nrf2
• Oxidative stress
• SHP
• Steatosis
• p62/SQSTM1

• live donor liver transplants (ldlt)
• transplant
• donor
• theory
• model

A hallmark of chronic liver disease is the impairment of the liver’s innate regenerative ability. In this work we use a computational approach to unravel the principles underlying control of liver repair following an acute physiological challenge.

We used a mathematical model of inter- and intra-cellular interactions during liver regeneration to infer key molecular factors underlying the dysregulation of multiple regeneration modes, including delayed, suppressed, and enhanced regeneration. We used model analysis techniques to identify organizational principles governing the cellular regulation of liver regeneration. We fit our model to several published data sets of deficient regeneration in rats and healthy regeneration in humans, rats, and mice to predict differences in molecular regulation in disease states and across species. 

Analysis of the computational model pointed to an important balance involving inflammatory signals and growth factors, largely produced by Kupffer cells and hepatic stellate cells, respectively. Our model analysis results also indicated an organizational principle of molecular regulation whereby production rate of molecules acted to induce coarse-grained control of signaling levels while degradation rate acted to induce fine-tuning control. We used this computational framework to investigate hypotheses concerning molecular regulation of regeneration across species and in several chronic disease states in rats, including fructose-induced steatohepatitis, alcoholic steatohepatitis, toxin-induced cirrhosis, and toxin-induced diabetes. Our results indicate that altered non-parenchymal cell activation is sufficient to explain deficient regeneration caused by multiple disease states. We also investigated liver regeneration across mammalian species. Our results suggest that non-invasive measures of liver regeneration taken at 30 days following resection could differentiate between several hypotheses about how human liver regeneration differs from rat regeneration.

Overall, our results provide a new computational platform integrating a wide range of experimental information, with broader utility in exploring the dynamic patterns of liver regeneration across species and over multiple chronic diseases.

The online version of this article (doi:10.1186/s12918-015-0220-9) contains supplementary material, which is available to authorized users.

• Dietary bioactive compounds
• Epigenetics
• Histone deacetylase
• Histones acetyltransferase

• Animals
• Blotting, Western
• Cell Proliferation/drug effects
• Choline/metabolism
• Diet
• Down-Regulation/drug effects
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Fatty Liver/metabolism
• Fatty Liver/physiopathology
• Fatty Liver/prevention & control
• Hepatectomy/methods
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Human Growth Hormone/administration & dosage
• Human Growth Hormone/blood
• Human Growth Hormone/deficiency
• Humans
• Liver/drug effects
• Liver/metabolism
• Liver/surgery
• Male
• Methionine/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Non-alcoholic Fatty Liver Disease
• Obesity/metabolism
• Obesity/physiopathology
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor/metabolism
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Signal Transduction/physiology
• Triglycerides/metabolism

• fatty liver
• liver regeneration
• lipotoxicity
• er stress

Nonalcoholic fatty liver disease (NAFLD) is a risk for hepatocellular carcinoma (HCC), but the association between a high-fructose diet and HCC is not fully understood. In this study, we investigated whether a high-fructose diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN).

Seven-week-old male Sprague–Dawley rats were fed standard chow (controls), a high-fat diet (54% fat), or a high-fructose diet (66% fructose) for 8 weeks. All rats were given DEN at 50 μg/L in drinking water during the same period. Precancerous hepatocytes were detected by immunostaining of the placental form of glutathione-S-transferase (GST-P). The number of GST-P-positive hepatocytes was assessed in liver specimens.

Serum levels of total cholesterol were similar among the three groups, but serum triglyceride, fasting blood glucose, and insulin levels were higher in the high-fructose group compared to the high-fat group. In contrast, hepatic steatosis was more severe in the high-fat group compared with the high-fructose and control groups, but the incidence of GST-P-positive specimens was significantly higher in the high-fructose group compared to the other two groups. The average number of GST-P-positive hepatocytes in GST-P positive specimens in the high-fructose group was also higher than those in the other two groups. This high prevalence of GST-P-positive hepatocytes was accompanied by higher levels of 8-hydroxydeoxyguanosine in serum and liver tissue.

These results indicate that dietary fructose, rather than dietary fat, increases the incidence of precancerous hepatocytes induced by administration of DEN via insulin resistance and oxidative stress in rat. Thus, excessive fructose intake may be a potential risk factor for hepatocarcinogenesis.

Age-related diseases such as type 2 diabetes, cardiovascular disease, and cancer involve epigenetic modifications, where accumulation of minute changes in the epigenome over time leads to disease manifestation. Epigenetic changes are influenced by life style and diets. This represents an avenue whereby dietary components could accelerate or prevent age-related diseases through their effects on epigenetic modifications. Histone acetylation is an epigenetic modification that is regulated through the opposing action of histone acetylases (HATs) and deacetylases (HDACs). These two families of enzymes play critical roles in metabolic processes and their dysregulation is associated with pathogenesis of several diseases. Dietary components, such as butyrate, sulforaphane, and curcumin, have been shown to affect HAT and HDAC activity, and their health benefits are attributed, at least in part, to epigenetic modifications. Given the decades that it takes to accumulate epigenetic changes, it is unlikely that pharmaceuticals could undo epigenetic changes without side effects. Therefore, long term consumption of dietary components that can alter the epigenome could be an attractive means of disease prevention. The goal of this review is to highlight the roles of diets and food components in epigenetic modifications through the regulation of HATs and HDACs for disease prevention.

• Acetylation
• Diet
• Epigenesis, Genetic
• Histone Acetyltransferases/metabolism
• Histone Deacetylases/metabolism
• Histones/metabolism
• Humans
• Metabolic Diseases/genetics
• Metabolic Diseases/metabolism
• Metabolic Diseases/prevention & control