Steatohepatitis Induced by Intragastric Overfeeding in Mice *

Abstract

Nonalcoholic steatohepatitis is prevalent among obese individuals with excessive caloric intake, insulin resistance, and type II diabetes. However, no animal models exist that recapitulate this important association. This study produced and characterized steatohepatitis (SH) caused by intragastric overfeeding in mice. C57BL/6, tumor necrosis factor (TNF) type I receptor-deficient, and genetically matched wild type mice were fed via an implanted gastrostomy tube a high-fat diet for 9 weeks in the increasing amount up to 85% in excess of the standard intake. Animals were examined for weight gain, insulin sensitivity, and histology and biochemistry of liver and white adipose tissue (WAT). Overfed C57BL/6 mice progressively became obese, with 71% larger final body weights. They had increased visceral WAT, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed SH with increased plasma alanine aminotransferase (121 ؎ 27 vs. 13 ؎ 1 U/L), neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Obese WAT showed increased TNF␣ and leptin expression and reciprocally reduced adiponectin expression. The expression of lipogenic transcription factors (SREBP-1c, PPAR␥, LXR␣) was increased, whereas that of a lipolytic nuclear factor PPAR␣ was reduced in SH. SH was associated with reduced cytochrome P450 (Cyp)2e1 but increased Cyp4a.

S‐Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate‐Deficient Diet

“…De novo fatty acid synthesis is regulated by the ER stress-associated transcription factor nSREBP-1c (Deng et al, 2005), whereas phosphorylation and activation of hepatic AMPK suppress the expression of hepatic SREBP-1c and its target lipogenic enzymes (Zhou et al, 2001). Previously, we found that SREBP-1c and its downstream-regulated genes FAS, ACC, and SCD were activated in ethanol-fed micropigs, correlating with reduced levels of the SAM to SAH ratio (Esfandiari et al, 2005).…”

Genome-wide transcriptome expression in the liver of a mouse model of high carbohydrate diet-induced liver steatosis and its significance for the disease

“…Since no changes in transcriptome expression of proinflammatory or profibrotic cytokines (e.g., TNF-a, IL-1b, IL-18, TGF-b, and others), classically thought to mediate liver injury including fibrosis, were identified in the HCD-fed mouse liver, it seems that these classic proinflammatory cytokines, at least those secreted in the liver, may not be critically involved in the early aspects of this disease. The lack of TNF-a participation in dietary-induced NASH was recently suggested by Deng et al [7], who demonstrated that knocking out the TNF-a receptor 1 does not prevent NASH induced by forcefeeding a fat-enriched diet. Similar studies by Dela Pena et al [26] showed that TNFR1 knockout mice still develop hepatic steatosis when fed a methionine-restricted, cholinedeficient diet.…”

“…Experimental models based on voluntary food intake have been developed to induce hepatic steatosis in laboratory animals [2][3][4][5][6][7][8]. The nutritional models using complete diets resemble the human condition in that they contain amounts of lipids or carbohydrates that exceed the energy needs of the body.…”

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

“…Although several animal models have been proposed, many of them are based on genetic defects or special diet-induced factors, so it is difficult to determine the exact disease process of NASH on the basis of metabolic syndrome alone. [7][8][9] We previously described a murine model of NASH induced by neonatal subcutaneous injection of monosodium glutamate (MSG), which includes the clinical manifestations of central obesity, diabetes, hyperlipidemia, and ultimately, liver inflammation, fibrosis, and liver tumor, similar to the manifestations that are present in the human liver. 10,11 Tsumura Suzuki obese diabetes (TSOD) mice are novel polygenic models of spontaneous type-2 diabetes mellitus that develop moderate degrees of obesity, especially apparent in animals more than 11 weeks of age.…”