Disrupted signaling and inhibited regeneration in obese mice with fatty livers: Implications for nonalcoholic fatty liver disease pathophysiology

Abstract

The impaired regenerative capacity of fatty livers might promote the progression of nonalcoholic fatty liver disease (NAFLD). To identify mechanisms involved, regenerative responses were compared in normal mice and ob/ob mice (a model for NAFLD) after partial hepatectomy (PH). We hypothesized that the usual PH activation of oxidant-sensitive, growth-regulatory kinase cascades would be abnormal in fatty hepatocytes, which have adapted to chronic oxidant stress, and expected that this might interfere with the induction of proliferative-and stress-related genes. The normal coordinated induction of Jun N-terminal kinases (Jnks) and extracellular regulated kinases (Erks) does not occur after PH in ob/ob mice, which cannot activate Jnks but can superinduce Erks. Jnk inhibition is associated with enhanced activation of Akt, which inhibits phosphoenolpyruvate carboxykinase ( Obesity and type 2 diabetes are risk factors for nonalcoholic fatty liver disease (NAFLD), 1-3 a spectrum of liver pathology that resembles alcohol-induced liver damage. 4 Fatty liver is the earliest and most prevalent stage of NAFLD. 5 Hepatic steatosis generally has a benign outcome, 6 but some individuals with this lesion develop progressive liver injury and eventually experience significant liver-related morbidity and increased mortality. 1 The mechanisms that promote disease progression in NAFLD are poorly understood. It has been suggested that more advanced stages of NAFLD might be triggered when an acute inflammatory insult, i.e., "second hit," is superimposed on hepatic steatosis. 7 Because healthy livers typically regenerate and recover completely from acute inflammation, 8 this suggests that the normal regenerative response to injury might be impaired in fatty livers.Hepatic regenerative capacity is often assessed experimentally by monitoring the response to PH. 8 Liver regeneration after two thirds (partial) hepatectomy (PH) is inhibited in obese, diabetic Zucker fa/fa rats with fatty livers, 9 supporting the concept that the liver's ability to regenerate is decreased in NAFLD. However, the mechanism(s) that impair liver regeneration in fatty livers have not been identified. The present study uses PH as a tool to compare the regenerative activation of oxidant-sensitive, growth-regulatory protein kinase cascades in genetically obese, ob/ob mice, an animal model for NAFLD, 10 and lean control mice. After PH, these enzymes are normally activated by cytokines and growth factors, 11,12 and their interactions help to orchestrate the changes in hepatocyte gene expression [13][14][15][16][17][18][19] that are required to maintain hepatocyte viability, 20,21 induce proliferation, 19,22-24 and preserve tissue-specific functions 18,19 during the regenerative response. We hypothesize that the normal, acute oxidant-mediated, activation of the mitogen-and stress-activated protein kinases will be disturbed in fatty livers, which over-produce oxidants chronically. 25 If this concept is confirmed, then secondary objectives are to identify possible mechani...

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

“…8,9 However, there is an interesting difference in leptin levels between HFD-fed models and genetic models of obesity. As previously mentioned, mice fed an HFD have increased leptin levels, due to an increased amount of adipose tissue.…”

“…[5][6][7][8][9] Nuclear factor-kappa B (NF-B), crucial for the priming phase of liver regeneration, has been shown to be involved in both of these processes, promoting hepatocyte proliferation and also inhibiting apoptosis of liver cells. [10][11][12][13][14][15] To study the effects of dietary-induced obesity on liver regeneration, we subjected mice fed a high-fat diet (HFD) to PHx.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Thus, it has been proposed that up-regulation of UCPs negatively impacts cellular energy conservation only when the availability of oxidizable substrates becomes limited, e.g. under conditions of acute stress like ischemia, partial hepatectomy, and lipopolysaccharide exposure [51,54,55]. Based on this information, further studies are required to elucidate the impact of obesity on hepatic mitochondrial physiology in vivo particularly in the context of whether mitochondria are coupled or un-coupled as a consequence of steatosis.…”

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…22,23 Suppression of fat accumulation in the liver after PH impairs LR in mice. 24 On the other hand, excessive liver steatosis, such as in leptin-and leptinreceptor-deficient mice [25][26][27] or high fat diet-fed mice, 28 also derails LR post PH. At the molecular level, ob/ob and high fat diet-fed mice show decreased expression of cyclin D1, and heightened p21 protein levels, 29 which recapitulates the molecular signature we identified in HET mice.…”