# Cholesterol, Its Metabolites, and Nonalcoholic Steatohepatitis

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

The metabolic pathways in nonalcoholic steatohepatitis (NASH) that contribute to fatty
liver’s progression to inflammation are being intensely studied. One pathway which has been
overlooked is the CYP27A1 initiated ‘alternative pathway.’ This pathway is responsible for the
metabolism of cholesterol to intracellular regulatory oxysterols. The pathway’s subsequent 7α-
hydroxylation of these oxysterols and their lipotoxic metabolites by CYP7B1 is what is believed
to eliminate their regulatory effects. However, what controls cell levels of these oxysterols and
their known metabolites remains incompletely defined. Furthermore, the potential for these
alternative pathway cholesterol metabolites in eliciting cytotoxicity and inflammation in fatty liver
has not been studied.
 A preliminary study in a ‘fatty liver’ mouse model showed that overexpression of the
mitochondrial cholesterol delivery protein, StARD1, increased mitochondrial CYP27A1
cholesterol metabolism, and, led to a dramatic reduction in hepatic cholesterol, triglycerides,
and free fatty acids levels. Unanticipated, we found significant down regulation of hepatic
CYP7B1 expression coupled with high levels of the regulatory oxysterols, 25-
hydroxycholesterol(25HC), 27-hydroxycholesterol(27HC), and 24(S)-hydroxycholesterol(24HC)
and a marked increase in LFTs. Based upon these observations, we postulated that low
CYP7B1 and increased oxysterol levels may represent a pathway to inflammation in fatty liver.
More specifically, chronic down-regulation of CYP7B1 leading to chronically increased oxysterol
levels may play a role in the transition from fatty liver to inflammation as seen in NASH.
Supportive of this hypothesis we found significant suppression of CYP7B1 expression
correlated to an increase in 27HC levels in human steatotic livers obtained from the NIH liver
tissue cell distribution system. Furthermore, in Western diet fed mice, we have now shown that
a low CYP7B1 is associated with an increase in 27HC levels and subsequent inflammasome
activation as determined by increased IL-1B levels; outlining a pathway from fatty liver to
inflammation as occurs in NASH. These observations also provided evidence for CYP7B1 being
a key regulator of the levels and ratio of the three CYP27A1 generated oxysterols
(24HC/25HC/27HC), and their hydroxylated metabolites
 In conclusion: we hypothesize that in nonalcoholic fatty liver (NAFL) there is chronic
suppression of CYP7B1. The chronic effects of increased levels of cholesterol metabolites as
controlled by down-regulated CYP7B1 have injurious effects, and represent the major driving
force for transition from NAFL to steatohepatitis via inflammasome activation. The means by
which CYP7B1 is suppressed in NAFL is unknown. We propose three specific aims to define
the pathway:
 Aim1: To define the CYP27A1 initiated ‘alternative pathway’ of oxysterol/BAS. More
specifically, more clearly define the pathway metabolites and quantitate their levels/ratios under
dif...

## Key facts

- **NIH application ID:** 9898208
- **Project number:** 5I01BX000197-11
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** WILLIAM M PANDAK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898208

## Citation

> US National Institutes of Health, RePORTER application 9898208, Cholesterol, Its Metabolites, and Nonalcoholic Steatohepatitis (5I01BX000197-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898208. Licensed CC0.

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