# A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $334,000

## Abstract

PROJECT SUMMARY
Fatty liver potentiates alcohol-associated liver disease (ALD) development. AKAP12 (A-kinase anchoring protein
12) is a scaffolding protein in signal transduction by anchoring protein kinases (PKA, PKC), cyclin-D1 and heat
shock protein 47. Our recent proteomics studies showed that AKAP12 exhibited decreased interaction with
kinases and increased interaction with phosphatases by alcohol in mouse models and human ALD. This led us
to examine whether alcohol regulated AKAP12 phosphorylation. By phospho-peptide mapping we determined
that alcohol strongly inhibited AKAP12 phosphorylation in mouse liver. AKAP12’s alcohol-sensitive phospho-
sites were mainly PKA-predicted substrates. Mutating these phospho-sites reduced the stability of AKAP12
protein, suggesting that phosphorylation stabilized AKAP12. The AKAP12 interactome revealed its interactions
with proteins known to regulate lipid homeostasis such as PKA, 2-adrenergic receptor (2-AR) and lipolytic
enzymes, adipose-triglyceride lipase (ATGL). We therefore assessed the functional role of this AKAP12
interactome in hepatocytes. It was shown previously that AKAP12-mediated PKA scaffolding recruits it to 2-
AR. The signalosome of AKAP12, PKA and 2-AR regulates cAMP levels through the process of 2-AR de-
sensitization/re-sensitization and may involve AKAP12 phosphorylation. 2-AR/PKA/cAMP signaling limits lipid
accumulation and enhances lipolysis. Our novel preliminary data indicates that alcohol exposure dysregulates
several components of the AKAP12/PKA/2-AR signalosome. Alcohol inhibited the interaction between PKA and
2-AR. AKAP12 was highly phosphorylated at a S696-S698 PKA-phospho-site that was previously published to
facilitate AKAP12-2-AR binding. This site exhibited decreased phosphorylation upon alcohol exposure and
mutating this AKAP12 site reduced its scaffolding towards both PKA and 2-AR. This AKAP12 mutation also
reduced 2-AR protein stability. Alcohol interfered with AKAP12-2-AR interaction and facilitated AKAP12 and
2-AR lysosomal degradation. Based on these data, we hypothesize that decreased AKAP12 phosphorylation
following alcohol exposure might interfere with AKAP12/PKA/2-AR signalosome, causing alterations in cAMP
signaling, which in turn could dysregulate lipid homeostasis. Preliminary data that support this hypothesis are:
1) Enhancing endogenous AKAP12 levels reverses the inhibitory effect of alcohol on PKA-2-AR interaction; 2)
AKAP12 induction inhibits alcohol-mediated increase of triglyceride levels; 3) AKAP12 induction reverses
alcohol’s suppressive effect on fatty acid oxidation. Induction of AKAP12 also reverses alcohol’s suppressive
effect on the activity of lipolytic enzyme, ATGL. Whether the AKAP12/PKA/2-AR scaffold controls lipid
homeostasis is unknown. We hypothesize that dysregulation of the AKAP12 signalosome favors lipid
accumulation. This proposal will evaluate how alcohol-sensitive AKAP12 phosphorylation destabilizes AKAP12,
impairs i...

## Key facts

- **NIH application ID:** 10705602
- **Project number:** 5R01AA029988-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Komal Ramani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $334,000
- **Award type:** 5
- **Project period:** 2022-09-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705602

## Citation

> US National Institutes of Health, RePORTER application 10705602, A-Kinase Anchoring Protein Dysregulation during Alcohol-Associated Liver Disease (5R01AA029988-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705602. Licensed CC0.

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