Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD

Abstract

Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels.

Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

“…The importance of visceral adipose tissue as site of chronic inflammation is further supported by some studies demonstrating that the lack of adipocyte 5′ AMP-activated protein kinase worsens insulin resistance and liver disease by affecting brown and beige adipose tissue function 163. Additionally, adipose tissue-specific insulin receptor knockout mice develop more severe NAFLD with histological evidence of ballooning degeneration further supporting the notion that the adipose tissue is of key importance in the development and progression of NAFLD 164. In contrast, recent research has found that adipose tissue type I interferon signalling may protect from metabolic dysfunction 165…”

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

“…Tissues were stored frozen or fixed in formalin, and sections were stained with H&E. Liver histology was graded by a board-certified veterinary pathologist blinded to the experimental conditions, and NAS was assessed as previously published (27). Triglycerides from liver samples were measured according to previously published methods (63). In brief, 100 mg of liver tissue was homogenized in 1 ml of chloroformmethanol (2:1 v/v).…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Genetic mouse models of lipodystrophy develop markedly depleted adipose stores, severe fatty liver disease and systemic insulin resistance (Saha et al 2004, Softic et al 2016. Due to limited adipose tissue lipid storage, patients with lipodystrophy frequently develop NAFLD and are at an increased risk for developing hypertriglyceridemia 234:1 and diabetes (Safar Zadeh et al 2013, Akinci et al 2015.…”