Management of Metabolic-Associated Fatty Liver Disease/Metabolic Dysfunction-Associated Steatotic Liver Disease: From Medication Therapy to Nutritional Interventions

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common long-lasting liver disease that affects millions of people around the world. It is best identified with a hepatic fat build-up that ultimately leads to inflammation and damage. The classification and nomenclature of NAFLD have long been a controversial topic, until 2020 when a group of international experts recommended substituting NAFLD with MAFLD (metabolic dysfunction-associated FLD). MAFLD was then terminologically complemented in 2023 by altering it to MASLD, i.e., metabolic dysfunction-associated steatotic liver disease (MASLD). Both the MAFLD and the MASLD terminologies comprise the metabolic element of the disorder, as they offer diagnostic benchmarks that are embedded in the metabolic risk factors that underlie the disease. MASLD (as a multisystemic disease) provides a comprehensive definition that includes a larger population of patients who are at risk of liver morbidity and mortality, as well as adverse cardiovascular and diabetes outcomes. MASLD highlights metabolic risks in lean or normal weight individuals, a factor that has not been accentuated or discussed in previous guidelines. Novel antihyperglycemic agents, anti-hyperlipidemic drugs, lifestyle modifications, nutritional interventions, and exercise therapies have not been extensively studied in MAFLD and MASLD. Nutrition plays a vital role in managing both conditions, where centralizing on a diet rich in whole vegetables, fruits, foods, healthy fats, lean proteins, and specific nutrients (e.g., omega-3 fatty acids and fibers) can improve insulin resistance and reduce inflammation. Thus, it is essential to understand the role of nutrition in managing these conditions and to work with patients to develop an individualized plan for optimal health. This review discusses prevention strategies for NAFLD/MAFLD/MASLD management, with particular attention to nutrition and lifestyle correction.

Keywords: cardiovascular diseases; diabetes; fatty liver disease; lifestyle; nutrition; obesity.

Figure 1

Therapy plans for MAFLD/MASLD management.

Figure 2

Effects of KD (i.e., consuming more fat and protein instead of carbohydrates) on the incidence and progression of hepatic conditions, compared to HFD and Chow. (A) Images taken from the liver sections (with scale bar = 100 μm), which are stained with H&D, cleaved caspase 3, and Gom and mass (for fibrosis). As shown, marked hepatic inflammation, ballooning of hepatocytes, and fibrosis are visible in mice fed with KD, compared to other treatments. Further, apoptotic hepatocytes can be found in KD-fed mice, suggestive of “caspase 3” activation in hepatocytes. (B) Lipid profile (i.e., distribution of lipid species in the pool of upregulated lipids, compared to the total pool). Under various treatments (i.e., KD vs. HFD vs. Chow), it can be seen that triglycerides (TGs) are overrepresented (compared to other species), suggestive of marked effect of KD on TGs. (C) Liver sections (stained with oil red O or H&S) (scale bar = 100 μm). As depicted, KD can potentially trigger IL-6 and JNK signaling pathway, which both are linked with glucose intolerance and HS. (KD: ketogenic diet; HFD: high-fat diet, IgG: immunoglobulin G; IL-6Ab: interleukin 6 antibody) [84]. This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

Figure 3

Effects of KDR (ketogenic diet; with 89.5% F, 0.1% C, 10.4% P), NCR (fed control normal chow of KDR; with 10% F, 70% C, 20% P), KDH (ketogenic diet’ with 91.3% 1% C, 7.7% P), and NCH (fed control normal chow of KDH; with 15.5% F, 64.5% C, and 20% P) diets on hepatic parameters in male C57BL/6J mice. (A,B) KDR triggers insulin resistance and impaired glucose homeostasis, more severely than other diets. (C,D) Hematoxylin and eosin (H&S) staining of the liver and epididymal adipose tissue (eAT) section and adipocyte area, implying higher scores of NAFLD and adipocyte size in mice fed with KDR and KDH (than NCH and NCR); these scores are higher in KDH than in KDR. F: Fat; C: Carbohydrates; P: Protein. (** p < 0.01; *** p < 0.001) [86]. This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

Figure 4

The HA diet (low fat + A. muciniphila) is supposed to alleviate HS, slow down weight loss, and relieve hepatic injury. It further mitigates “adiposity” and “alteration of adipokines”, both of which are contributors to MAFLD pathogenesis. Overall, the size of the total white adipose tissue (WAT) is reduced in HA-fed mice. Specifically, the size of the epididymal WAT tissue (eWAT) is reduced in the HA diet (compared to the HP diet = high fat) (A), while treatment with HA (compared to HP) reduces the size of adipocytes (B). Notably, one of the hallmarks of MAFLD is highly permeable intestinal barriers, which enhance the risk of systemic inflammation due to over transportation of bacteria (and bacterial products) and commensal metabolites. As shown in (C), the HA diet makes the “mucus layer and tight junctions” thicker (compared to the thinner layer in HP-fed mice). These suggest “A. muciniphila” as a potent probiotic that can bring beneficial outcomes and is worth exploring in future human clinical trials [100]. HA (low fat + A. muciniphila), HP (high fat), LP (low fat), WAT, eWAT. This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

Figure 5

Mechanisms and enzymes involved in the development of HS, and therapy options which can avoid MAFLD (and subsequent NASH, cirrhosis, and HCC). Note that the content in this figure is only suggestions and needs to be approved in clinical trials [103]. HS: hepatic steatosis; MAFLD: metabolic dysfunction–associated FLD; NASH: non–alcoholic steatotic hepatis; AST: aspartate transaminase alanine; ALT: alanine transaminase; DNL: de novo lipogenesis; FAS: fatty acid synthase; SCD1: stearoyl–CoA desaturase; PPAR–α: peroxisome proliferator-activated receptor–α; FAs: fatty acids; ROS: reactive oxygen species; BMI: body mass index; HCC: hepatocellular carcinoma. This content is distributed under the terms of the Creative Commons Attribution 4.0 International license.

Figure 6

The Mediterranean diet (MD), its food components, and benefits for MAFLD patients. MD: Mediterranean diet; TRF: time-restricted feeding; BMI: body mass index; WC: waist circumference; T2DM: type 2 diabetes mellitus; MAFLD: metabolic dysfunction-associated fatty liver disease.