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Estrogen-SAM-m6A axis: a novel mechanism of protection against MASLD

Award Number: F30DK145167
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Estrogen-SAM-m6A axis: a novel mechanism of protection against MASLD - ABSTRACT It is well known that premenopausal females are relatively protected against metabolic dysfunction- associated steatotic liver disease (MASLD) compared to postmenopausal females and males. Based on these observations and other preliminary studies, estrogen has been implicated in protecting against hepatic steatosis. However, without understanding the specifics of estrogen function in the liver, no targeted therapies based on this mechanism can be developed. Recently, N6-methyladenosine (m6A) RNA methylation in male mice has been shown to be protective against MASLD, and higher levels of m6A have been associated with decreased lipogenesis and hepatic steatosis. Our data in steatotic high fat diet (HFD) male mice supports this finding by demonstrating their decreased global m6A levels compared to healthy mice. On the other hand, females on HFD do not develop hepatic steatosis and their m6A levels remain relatively high. Female mice on HFD also display higher levels of the m6A precursor, i.e. S-adenosylmethionine (SAM), compared to HFD males. Furthermore, our experiments show that several enzymes of the methionine cycle, which serves to generate SAM, are estrogen dependent and are higher in females compared to males on HFD. Despite these findings, it is currently not known if estrogen, SAM and m6A RNA methylation are synergistic components of one mechanism that serves to protect young females on HFD against steatosis. We hypothesize that relatively high levels of estrogen in HFD female mice lead to increased availability of methyl donor SAM and more abundant m6A RNA methylation compared to low estrogen models on HFD. This proposal is significant because, if true, it would imply that upregulation of this estrogen-SAM-m6A axis might be protective against the development of hepatic steatosis. To test this hypothesis, we will first establish regulation of SAM availability and m6A methylation by estrogen. We will then validate that rescue of SAM is sufficient to rescue global m6A levels, as well as m6A methylation of specific lipogenic genes on HFD. Completion of the proposed experiments will establish a novel estrogen – SAM – m6A axis in the liver, which has strong implications in MASLD protection. While it is known that estrogen and m6A RNA methylation are protective against hepatic steatosis on a high fat diet, we do not know whether they are synergetic components of one pathway. My project will answer this question, thereby uncovering a novel biological mechanism that can be utilized as a basis for MASLD treatment in the future.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $55,114 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/8/2026	NEW	$55,114
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/8/2026	NEW	$0
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Estrogen-SAM-m6A axis: a novel mechanism of protection against MASLD

Award Number: F30DK145167

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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