Lipoprotein subclass metabolism in nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver. In addition, increased cholesterol content in the liver associates with NASH. Here we study the association of lipoprotein subclass metabolism with NASH. To this aim, liver biopsies from 116 morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, BMI 45.1 ± 6.1 kg/m², 39 men and 77 women] were used for histological assessment. Proton NMR spectroscopy was used to measure lipid concentrations of 14 lipoprotein subclasses in native serum samples at baseline and after obesity surgery. We observed that total lipid concentration of VLDL and LDL subclasses, but not HDL subclasses, associated with NASH [false discovery rate (FDR) < 0.1]. More specifically, total lipid and cholesterol concentration of VLDL and LDL subclasses associated with inflammation, fibrosis, and cell injury (FDR < 0.1), independent of steatosis. Cholesterol concentration of all VLDL subclasses also correlated with total and free cholesterol content in the liver. All NASH-related changes in lipoprotein subclasses were reversed by obesity surgery. High total lipid and cholesterol concentration of serum VLDL and LDL subclasses are linked to cholesterol accumulation in the liver and to liver cell injury in NASH.

Keywords: high density lipoprotein; lipids; lipoproteins/metabolism; liver; low density lipoprotein; nuclear magnetic resonance; obesity; obesity surgery; very low density lipoprotein.

Fig. 1.

Lipoprotein subclass lipid concentration in individuals divided into groups by liver phenotype divided to those with normal liver histology (n = 32), simple steatosis without inflammation and cell injury (n = 19) and to those with NASH (n = 25) (A), steatosis grade (B), lobular inflammation (C), and fibrosis stage (D). Percentage changes comparing to the group without the pathology (set to 0%) have been calculated. Statistical significance over all groups (normal and all degrees of pathology in each panel) are visualized with FDR < 0.05 (*) and FDR < 0.01 (#) compared with individuals without the pathology below the horizontal axis in each panel. The color of the symbol indicates subgroup analysis comparing a given group to the group without pathology (gray indicates P < 0.05, black indicates P < 0.01).

Fig. 2.

A: Lipoprotein subclass cholesterol concentration in individuals with NASH compared with those with normal liver histology. Percentage changes comparing to the group without the pathology (set to 0%) have been calculated and statistical significance is shown as in Fig. 1. Spearman correlation between lipoprotein subclass cholesterol concentration and liver cholesterol content (B) and liver free cholesterol content (C) (black bars, P < 0.05).

Fig. 3.

Changes in lipoprotein subclass lipid concentrations (A) in response to RYGB in the whole study group compared with baseline. B: Shows the effect of RYBG specifically in individuals with NASH by showing the difference between the NASH group and the normal group at baseline (squares) and the NASH group after RYGB compared with the normal group at baseline (triangles). The color of the symbol indicates subgroup analysis comparing a given group to the group without pathology (A) or to baseline (B) (gray indicates P < 0.05, black indicates P < 0.01).