# Novel Cellular Mechanisms for Reducing Hyperlipidemia

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2020 · —

## Abstract

The liver plays a central role in whole-body lipid metabolism by regulating the uptake, synthesis, oxidation
and export of fatty acids (FAs) and lipids. Dysfunction of lipid metabolism in liver underlies the development
of obesity, diabetes, nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease. Although the
mechanisms that regulate the hepatic uptake, activation, and metabolism of fatty acids (FAs) are not fully
understood, nearly all pathways of FA metabolism require conversion of FAs to acyl-CoAs by acyl-CoA
synthetases. Long chain acyl-CoA synthetase (ACSL) is a family of five enzymes (ACSL1, 3, 4, 5 and 6)
that catalyze the formation of fatty acyl-CoAs from ATP, CoA, and long chain fatty acids. Within ACSL
family members, ACSL4 has unique substrate specificity for arachidonic acid (AA) and hepatic ACSL4 has
been demonstrated being abnormally expressed in pathological conditions including hepatocarcinoma and
NAFLD. However, to date, no literature reports have clearly defined the specific roles played by ACSL4 in
liver lipid metabolism under normal and disease state such as the benign form of NAFLD (steatosis) and the
nonalcoholic steatohepatitis (NASH). During the last funding period, we have obtained two major findings
related to the regulation of hepatic ACSL4. First, we demonstrated that expression and activity of hepatic
ACSL4 are upregulated by activators of peroxisome proliferator-activated receptor  (PPAR) in vivo and in
vitro. Through conducting lipidomic studies we further demonstrated that depletion of ACSL4 in hepatic cells
selectively reduced cellular contents of several PC species including PC(18:0/18:1), a critical lipid mediator
in PPAR signaling pathway. Second, we uncovered a novel substrate-induced posttranslational regulatory
mechanism by which AA specifically downregulates ACSL4 protein abundance in hepatic cells by promoting
its ubiquitination and proteasomal degradation. Since AA-derived eicosanoids have been implicated in the
pathogenesis of NAFLD, the AA-induced ACSL4 degradation could be one contributing factor to the
progression of hepatic steatosis to NASH with increased hepatic inflammation caused by imbalance
between AA-CoA and unesterified AA that leads to increased production of AA-derived eicosanoids.
Recently, through proteomic studies, we have identified the intracellular vesicular transport factor p115 as a
major ACSL4 interacting protein and demonstrated that p115 interaction with ACSL4 is markedly enhanced
by exposure of HepG2 cells to AA but not to other FAs. Since AA specifically induces ACSL4 degradation,
our observations suggest that p115 might be a key mediator in the process of ACSL4 degradation through
ubiquitin-proteasomal pathway (UPP). The overall goals of this revised Merit Review Renewal are to fully
characterize two new regulatory mechanisms that uniquely impact the expression and function of ACSL4 in
liver tissue to reach a better understanding of its specific roles in hepati...

## Key facts

- **NIH application ID:** 9814671
- **Project number:** 5I01BX001419-08
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** FREDRIC B. KRAEMER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-01-01 → 2020-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814671

## Citation

> US National Institutes of Health, RePORTER application 9814671, Novel Cellular Mechanisms for Reducing Hyperlipidemia (5I01BX001419-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814671. Licensed CC0.

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