Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high-calorie diet

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the commonest liver diseases in Western countries. Although leptin deficient ob/ob and db/db mice are frequently used as murine models of NAFLD, an exhaustive characterization of their hepatic lesions has not been reported to date, particularly under calorie overconsumption. Thus, liver lesions were characterized in 78 ob/ob and db/db mice fed either a standard or high-calorie (HC) diet, for one or three months. Steatosis, necroinflammation, apoptosis and fibrosis were assessed and the NAFLD activity score (NAS) was calculated. Steatosis was milder in db/db mice compared to ob/ob mice and was more frequently microvesicular. Although necroinflammation was usually mild in both genotypes, it was aggravated in db/db mice after one month of calorie overconsumption. Apoptosis was observed in db/db mice whereas it was only detected in ob/ob mice after HC feeding. Increased apoptosis was frequently associated with microvesicular steatosis. In db/db mice fed the HC diet for three months, fibrosis was aggravated while steatosis, necroinflammation and apoptosis tended to alleviate. This was associated with increased plasma β-hydroxybutyrate suggesting an adaptive stimulation of hepatic mitochondrial fatty acid oxidation (FAO). Nevertheless, one-third of these db/db mice had steatohepatitis (NAS ≥ 5), whereas none of the ob/ob mice developed non-alcoholic steatohepatitis under the same conditions. Steatosis, necroinflammation, apoptosis and fibrosis are modulated by calorie overconsumption in the context of leptin deficiency. Association between apoptosis and microvesicular steatosis in obese mice suggests common mitochondrial abnormalities. Enhanced hepatic FAO in db/db mice is associated with fibrosis aggravation.

Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

“…In animal models, the presence or absence (and relevance) of hepatocyte ballooning is debated. It has been previously observed in mice and toxin-induced rat models of NASH (9,18), and in a recent elegant swine model of NASH (23); however, in our hands, as in others, the criteria according to the pathologist for ballooning were not met by simple but routine histochemical staining, agreeing with previous pathological examinations (40). A more detailed examination of hepatocyte ballooning, for example via K8/K18 immunostaining of liver sections, would be warranted to confirm this observation.…”

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

“…One of the major advantages of these genetic murine models of obesity is the rapid and consistent occurrence of insulin resistance, hyperglycemia, and NAFLD (Lindström, 2007;Trak-Smayra et al, 2011;Massart et al, 2012), whereas high-fat diet-induced obesity is not always associated with these secondary metabolic disorders, even after several months of feeding (Burcelin et al, 2002;Begriche et al, 2008a). It is noteworthy that both ob/ob and db/db mice are characterized by "borderline NASH," because fatty liver is associated with moderate hepatic necroinflammation and mild fibrosis Begriche et al, 2008b;Trak-Smayra et al, 2011). Moreover, this study and previous investigations (Trak-Smayra et al, 2011) showed comparable basal levels of plasma transaminases between ob/ob and db/db mice, indicating a similar degree of hepatic cytolysis.…”

“…Several predisposing factors could enhance the risk and the severity of APAP-induced acute liver failure, including malnutrition, alcoholic liver disease, hepatitis C virus infection, and nonalcoholic fatty liver disease (NAFLD), which is often associated with obesity and type 2 diabetes (Nguyen et al, 2008;Myers and Shaheen, 2009). NAFLD encompasses a large spectrum of liver lesions such as fatty liver, nonalcoholic steatohepatitis (NASH), and cirrhosis (Diehl, 2002;Trak-Smayra et al, 2011). It is noteworthy that hepatic CYP2E1 activity is frequently enhanced in obese individuals with NAFLD (Chalasani et al, 2003;Aubert et al, 2011) and in type 2 diabetics (Wang et al, 2003).…”

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

“…mild fibrosis (44)(45)(46)(47). We analyzed the hepatocyte ploidy profile by flow cytometry (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI73957DS1).…”