Desmosterol in Human Nonalcoholic Steatohepatitis

Abstract

Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 6 8.1 years [mean 6 standard deviation, SD], body mass index [BMI] 45.0 6 6.1 kg/m 2 ). Serum and liver levels of cholesterol precursors were measured with gas-liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 6 5.8 years, BMI 27.1 6 4.0 kg/m 2 ). Serum desmosterol levels and the desmosterol-tocholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology (P 5 0.002 and P 5 0.003, respectively). Levels of serum and liver desmosterol correlated strongly (r 5 0.667, P 5 1 3 10 29 ), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver (P < 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels (P 5 2 3 10 26 ) and the serum desmosterol-tocholesterol ratio (P 5 5 3 10 25 ) were associated with serum ALT in the population study. Conclusion: Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated. (HEPATOLOGY 2013;58:976-982)

Statin use and non-alcoholic steatohepatitis in at risk individuals

“…However, our findings are in line with previous evidence indicating that statins are generally well tolerated in patients with NAFLD, and may improve liver-related outcomes modulating the metabolism of both cholesterol and triglycerides [13][14][15][16][17][25][26][27][28][29][30].…”

“…Furthermore, insulin sensitizing agents and antioxidants have so far provided disappointing results in the treatment of this condition [12]. NASH is characterized by increased hepatic free cholesterol accumulation, reflecting dietary factors and insulin resistance [13,14], paralleled by increased expression and activity of 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase (HMGCR), the rate-limiting enzyme in cholesterol biosynthesis [14][15][16]. Furthermore, in severely obese, hepatic cholesterol content correlates with liver damage severity [17].…”

FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue

“…BMI, levels of serum total TGs, LDL-cholesterol, fasting plasma glucose, and insulin decreased, and the level of HDL-cholesterol increased, in response to surgery ( P < 0.05, Table 1 ), as previously published in the same cohort ( 18,19 ).…”

Protective Role of Plant Sterol and Stanol Esters in Liver Inflammation: Insights from Mice and Humans

“…Considering the beneficial effects of plant sterol and stanol esters on cholesterol metabolism, we hypothesized that consumption of plant sterol and stanol esters will lead to reduced hepatic inflammation. In addition, the recent observation that serum desmosterol concentrations were elevated exclusively in NASH but not in NAFLD patients [5] together with the recent finding of Spann et al [6] suggesting a prominent role for desmosterol as a master regulator of inflammation in macrophages prompted us to test this idea by measuring the same precursor concentrations not only in the livers of the HFD fed mice but also in another cohort of 57 severely obese patients (i.e. patients were classified as control (<5% steatosis), NAFLD or NASH).…”