A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Cells. 2020 Sep 1;9(9):2014. doi: 10.3390/cells9092014.


Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr-/-. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr-/-. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.

Keywords: NAFLD; NASH; animal model; atherosclerosis; fibrosis; inflammation; metabolic syndrome.

MeSH terms

  • Animals
  • Atherosclerosis / blood*
  • Atherosclerosis / drug therapy
  • Atherosclerosis / etiology*
  • Atherosclerosis / genetics
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / therapeutic use
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal*
  • Fast Foods / adverse effects*
  • Hyperinsulinism / drug therapy
  • Hyperinsulinism / etiology
  • Hyperlipidemias / drug therapy
  • Hyperlipidemias / etiology
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / blood*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Obesity / blood
  • Obesity / drug therapy
  • Obesity / etiology
  • Receptors, LDL / genetics
  • Transcriptome
  • Treatment Outcome


  • Receptors, LDL
  • obeticholic acid
  • Chenodeoxycholic Acid