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.
Highlights
Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver
Obese patients were divided into four groups based on severity of steatosis; into three groups based on lobular inflammation; and into three groups based on fibrosis stage
Because high VLDL cholesterol is linked with increased cholesterol synthesis in the liver, we explored mRNA expression of genes regulating cholesterol synthesis (CYP51A1, 7-dehydrocholesterol reductase (DHCR7), 24-dehydrocholesterol reductase (DHCR24), HMG-CoA reductase (HMGCR), lanosterol synthase (LSS), methylsterol monooxygenase (SC4MOL), SC5D, sterol regulatory element binding transcription factor 1a (SREBP1a), sterol regulatory element binding transcription factor 1c (SREBP1c), sterol regulatory element binding transcription factor 2 (SREBP2), and transmembrane 7 superfamily member 2 (TM7SF2)) and uptake (LDLR) in the liver
Summary
Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver. 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. Total lipid and cholesterol concentration of VLDL and LDL subclasses associated with inflammation, fibrosis, and cell injury (FDR < 0.1), independent of steatosis. 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.—Männistö, V. Cholesterol synthesis is increased in NAFLD [8], and cholesterol accumulation has been suggested to contribute to liver cell injury in NASH [9]. The related overproduction of VLDL particles in the metabolic syndrome [10] and NAFLD [4] has been thought to be a consequence of this
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